Novel therapeutic agents for the treatment of cancer, metabolic diseases and skin disorders

ABSTRACT

The present invention is directed to compounds having the structure (I) wherein R 1 , R 2 , R 3 , R 4 , R 5  and m are as defined herein. The compounds of this invention are novel therapeutic agents for the treatment of cancer, metabolic diseases and skin disorders in mammalian subjects. These compounds are also useful modulators of gene expression. They exert their activity by interfering with certain cellular signal transduction cascades. The compounds of the invention are thus also useful for regulating cell differentiation and cell cycle processes that are controlled or regulated by various hormones or cytokines. In particular, the invention relates to compounds that induce apoptosis of cancer cells and therefore may be used for the treatment or prevention of cancer, including advanced cancers and pre-cancerous cells. The invention also discloses pharmaceutical compositions and methods of treatment of disease in mammals.

FIELD OF INVENTION

The invention relates generally to a novel class of retinoids and morespecifically to methods of preparation, pharmaceutical compositions, andmethods of disease treatment utilizing pharmaceutical compositionscomprising these compounds.

BACKGROUND OF THE INVENTION

Cancer is a complex disease characterized by genetic mutations that leadto uncontrolled cell growth. Cancerous cells are present in allorganisms and under normal circumstances their excessive growth istightly regulated by various physiological factors. One such regulatoryprocess is apoptosis or programmed cell death. When the internalmachinery of a cell detects abnormalities in cell division and growth, asignal is propagated within the cell, activating suicide proteins thatkill the afflicted cell and prevent its proliferation. Such an apoptoticsignal can be triggered, for example, when a ligand or drug interactswith a receptor or protein in the cell.

Most agents that induce apoptosis in cancer cells (e.g. Doxorubicin andVincristine) are extremely toxic and cause a number of undesirable sideeffects. The toxicity associated with these therapies is a result of thenon-specific interaction of the drug with the DNA of non-cancerous cells(e.g. intestinal and red blood cells). In order to circumvent suchundesirable side effects, more selective compounds have been designedthat inhibit one or more signaling proteins, growth factors and/orreceptors involved in cancer cell proliferation. Examples includemonoclonal antibodies for breast cancer (e.g. Herceptin) andNon-Hodgkin's Lymphoma (e.g. Rituxan), as well anti-angiogenic drugs forchronic myeloid leukemia (e.g. Gleevec). Since patient populations aregenetically heterogeneous, it follows that a single selective therapywill not work in all cases, and as a result, cancer drugs are often usedin combination. As such, there is a continual need for improvedtreatments.

Retinoids are analogs of vitamin A and regulate cell growth,differentiation, and apoptosis. Retinoids bind to and activate twoclasses of Nuclear Retinoid receptors: the retinoic acid receptors(RARα, RARβ, RARγ) and retinoic X receptors (RXRα, RXRβ, RXRγ). Thesereceptors bind to specific sequences of DNA and thereby regulate geneexpression. The RAR and RXR receptor isoforms are expressed differentlyduring development and differentiation. These various isoforms caneither homodimerize or heterodimerize leading to a variety of proteincomplexes that regulate different sets of retinoid-induced genes.Activation of each receptor class results in modulation of variousbiological functions such as cell differentiation, embryonicdevelopment, and cell proliferation. Clinical studies have shown thatretinoic acid and its synthetic analogs can inhibit the growth andinvasion of cancer cells, and induce them to undergo apoptosis, therebyeradicating various types of cancers.

The novel compounds of this invention modulate the activity of NuclearRetinoid receptors. These novel compounds are thus useful for regulatingcell differentiation and cell cycle processes as well as other cellularsignaling processes controlled or regulated by hormories and vitaminssuch as the thyroid hormone, vitamin D, all-trans retinoic acid and9-cis-retinoic acid. Hence, conditions and/or diseases that areregulated by the aforementioned entities may be treated using thecompounds of this invention. Examples of such conditions include forexample cancer, mammary cancer, prostate cancer, kidney cancer,Karposi's sarcoma, colon cancer, cervical cancer, lung cancer, cutaneousT-cell lymphoma, cancer of the head and neck, cancers of theaerodigestive pathway, skin cancer, bladder cancer, sarcomas,leukoplakias, acute promyelocytic leukemia, acne, psoriasis, aging,wrinkling, diabetes, hyperglycemia, bone calcification, thyroidconditions, and the like.

Compounds that modulate the activity of RAR receptors are structuralanalogs of all-trans-retinoic acid. On the other hand compounds thatmodulate the activity of RXR receptors are structural analogs of9-cis-retinoic acid (e.g. Bexarotene). The aforementioned modulators ofNuclear Retinoid receptors bear a carboxylic acid group in a specificposition of the molecule. This acidic group forms a salt bridge to abasic residue in the binding pocket of the Nuclear Retinoid receptors.Research in this field indicates that removal of this acidic groupdrastically reduces the potency or the modulator. There are however,other amino acid residues in the binding pocket that can interact withthe modulator. None of the modulators of Nuclear Retinoid receptorsdescribed to date take advantage of these critical interactions.

Another drawback of the current state of the art is the limited aqueoussolubility of the selective Nuclear Retinoid receptor modulators. Saidmodulators mimic the structures of retinoic acids in order to conform tothe three-dimensional structure and the hydrophobic nature of therespective binding pockets. In general, introduction of solubilizingsubstituents has resulted in lower in vitro binding affinity orincreased in vivo metabolism and toxicity.

There exists therefore a need to improve upon the prior art in order toenhance the clinical profile of such therapeutics. Such improvements maybe carried out by introducing specially designed functional groups atspecific positions on the molecular backbone of the modulator. The novelcompounds of this invention address this issue and display enhanced invitro profiles when compared to compounds of the prior art.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the growth inhibitory effect of 4 compounds on humarihead and neck squamous cell carcinoma cells (SCC 103). The figureclearly shows the enhanced activity of example 5, example 6 and example8 when compared to Bexarotene(4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-benzoicacid).

SUMMARY OF THE INVENTION

Relative to prior art, this invention provides novel therapeutic agentsfor the treatment of cancer, metabolic diseases and skin disorders inmammalian subjects. These novel agents bear specially designedfunctional groups at specific positions on the molecular backbone of themodulator. Such improvements result from non-obvious modifications ofthe compounds of the prior art. These modifications provide additionalinteractions between the compounds of this invention and certain aminoacid residues in the binding pocket of the Retinoid Nuclear receptors.As a result, the compounds of this invention show enhanced in vitroprofiles when compared to compounds of the prior art.

The invention also provides novel compounds that interact with one ormore cellular receptors and are useful in the modulation of geneexpression.

Furthermore, the invention also provides novel compounds that are usefulin controlling cell cycle, and cell differentiation processes regulatedby certain hormones, such as for example.the thyroid hormone and thelike, and/or certain vitamins, such as for example vitamin D and thelike, and/or certain retinoids, such as for example 9-cis-retinoic acidand the like.

Furthermore, the invention also provides novel compounds that are usefulin inducing apoptosis in mammalian cells.

Furthermore, the invention also provides novel chemical compositions anddiscloses synthetic methodologies to prepare the same.

In one aspect, then, the invention relates to novel compounds having thestructural formula A

wherein:

-   R₁ is selected from the group consisting of compounds having    formulae A₁, A₂, A₃, A₄, A₅, and A₆-    wherein:    -   Z is selected from the group consisting of CH, and nitrogen. Y₃        is selected from the group consisting of C₂₋₈ alkyl, and C₂₋₈        substituted alkyl. R₆ is selected from the group consisting of        —OH, alkyloxy, aryloxy, alkylcarboxy, arylcarboxy, —SH,        alkylthio, arylthio, —NH₂, alkylamino, arylamino,        N-aryl-N-alkylamino, —NHNH₂, alkylhydrazino, arylhydrazino,        N-aryl-N-alkylhydrazino, —NHOR₁₇, —O(P═O)(OR₁₇)(OR₁₈),        —OCH₂O(P═O)(OR₁₇)(OR₁₈), and —OSO₃R₁₇. R₇ is selected from the        group consisting of hydrogen, halogen, and alkyl. R₁₅ and R₁₆        are independently selected from the group consisting of —OH,        alkyloxy, aryloxy, —NH₂, alkylamino, arylamino,        N-aryl-N-alkylamino, —NHNH₂, alkylhydrazino, arylhydrazino,        N-aryl-N-alkylhydrazino, —NHOR₁₇, alkyl, and aryl. R₁₇ and R₁₈        are independently selected from the group consisting of        hydrogen, alkyl, and aryl, and “**” represents the point of        attachment of the R₁ to the molecule of formula A;    -   R₂ is selected from the group consisting of    -    wherein:    -   R₈, R₉, R₁₀ and R₁₁ are independently selected from the group        consisting of hydrogen, halogen and alkyl. Y₁ and Y₂ are        independently O, S, NH, or CH₂, or Y₁ is O, S or NH, and Y₂ is        CH₂, with the proviso that Y₁ and Y₂ cannot both be O S, or NH        if n is 0 or 1, and “*” represents the point of attachment of        the R₂ to the molecule of formula A    -   R₃ substituents are independently selected from the group        consisting of halogen, alkyl, and alkyloxy.    -   R₄ is selected from the group consisting of alkyl, aryl,        heteroaryl, and adamantyl; R₅ is selected from the group        consisting of alkyl, alkyloxy, alkylthio, aryl, and heteroaryl;        or R₄ and R₅ may be linked together to form a substituted or        unsubstituted 5- or 6-membered cycloalkyl or cycloalkenyl ring,        where said substituents are selected from the group consisting        of —OH, ═O, halogen, alkyl, and where 1 or 2 of the carbon atoms        on said 5- or 6-membered cycloalkyl or cycloalkenyl ring may be        optionally replaced by W where W is selected from the group        consisting of O, S, N, NH, alkylamino, and arylamino.    -   m and n are independently 0, 1, 2 or 3, and pharmaceutically        acceptable salts thereof.

The non-limiting examples shown in schemes 1-4, illustrate theinventors' preferred methods for carrying out the preparative process ofthe invention.

In another aspect, the invention relates to pharmaceutical compositionscontaining the novel compounds of the invention and to methods of usingthese compounds for modulating and controlling cell cycle, celldifferentiation and apoptosis processes regulated by certain hormones,such as for example the thyroid hormone and the like, and/or certainvitamins, such as for example vitamin D and the like, and/or certainretinoids, such as for example 9-cis-retinoic acid and the like.

In another aspect, the invention relates to pharmaceutical compositionscontaining the novel compounds of the invention and to methods of usingthese compounds for modulating and controlling cell cycle, celldifferentiation and apoptosis processes regulated by certain genes, suchas for example the Fibroblast Growth Fact Binding Protein mRNA, and thelike, and/or certain Signal Transducers and Activators of Transcription,such as for example STAT3, and the like, and/or certain proteins, suchas for example Cyclin Dependent Kinase (CDK), Transforming Growth Factoralpha (TGF-α), and the like, and/or certain receptors, such as forexample Transforming Growth Factor Receptor (TGFR), Endothelial GrowthFactor Receptor (EGFR), Retinoid X Receptor (RXR) and the like.

In another aspect, the invention relates to pharmaceutical compositionscontaining the novel compounds of the invention and to methods of usingthese compounds to modulate selective gene expression by one or morecellular receptors.

In another aspect, the invention relates to pharmaceutical compositionscontaining the novel compounds of the invention and to methods oftreating diseases and/or conditions using the same. Examples of suchdisorders include proliferative disorders, differentiation disorders,cancer, inflammatory diseases, cardiovascular diseases, plasma HDLlevels, apolipoprotein A1 metabolism, hyperlipidemia, lipid metabolism,lipid homeostasis, hyperlipidemia, skin-related processes, autoimmunediseases, fatty acid metabolism, malignant cell development,premalignant lesions, programmed cell death, endocrinological processes,AP-1 metabolism and the like.

In another aspect, the invention relates to pharmaceutical compositionscontaining the novel compounds of the invention and to methods oftreating diseases and/or conditions using the same. Example of diseasesand/or conditions include cancer, mammary cancer, prostate cancer,kidney cancer, Karposi's sarcoma, colon cancer, cervical cancer, lungcancer, cutaneous T-cell lymphoma, cancer of the head and neck, cancersof the aerodigestive pathway, skin cancer, bladder cancer, sarcomas,leukoplakias, acute promyelocytic leukemia, acne, psoriasis, aging,wrinkling, diabetes, hyperglycemia, bone calcification, thyroidconditions, and the like.

In yet another aspect, the invention relates to pharmaceuticalcompositions containing the novel compounds of the invention incombination with other therapeutic agents and to methods of treatingdiseases and/or conditions using the same. Example of diseases and/orconditions include cancer, mammary cancer, prostate cancer, kidneycancer, Karposi's sarcoma, colon cancer, cervical cancer, lung cancer,cutaneous T-cell lymphoma, cancer of the head and neck, cancers of theaerodigestive pathway, skin cancer, bladder cancer, sarcomas,leukoplakias, acute promyelocytic leukemia and the like. Examples ofother therapeutic agents include Busulfan, Carboplatin, Cisplatin,Cyclophosphamide, Cytosine arabinoside, Etoposide, 5-Fluorouracil,Melphalan, Methotrexate, Mitoxantrone, Taxol, Interferon, Fareston,Arzoxifene, Evista, Tamoxifen, and the like.

The invention further provides pharmaceutical compositions containingone or more of the novel compounds as well as pharmaceuticallyacceptable pro-drugs and salts of such compounds.

Additional objects, advantages and novel features of the invention willbe set forth in part in the detailed description which follows, and inpart will become apparent to those skilled in the art upon examinationof the following, or may be learned by practice of the invention.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the invention, there are provided compounds havingthe structural formula A:

wherein:

-   a. R₁ is selected from the group consisting of structural formulae    A₁, A₂, A₃, A₄, A₅, and A₆-    with:    -   i) Z is selected from the group consisting of CH, and nitrogen    -   ii) Y₃ is selected from the group consisting of C₂₋₈ alkyl, and        C₂₋₈ substituted alkyl    -   iii) R₆ is selected from the group consisting of —OH, alkyloxy,        aryloxy, alkylcarboxy, arylcarboxy, —SH, alkylthio, arylthio,        —NH₂, alkylamino, arylamino, N-aryl-N-alkylamino, —NHNH₂,        alkylhydrazino, aryihydrazino, N-aryl-N-alkylhydrazino, —NHOR₁₇,        —O(P═O)(OR₁₇)(OR₁₈), —OCH₂O(P═O)(OR₁₇)(OR₁₈), and —OSO₃R₁₇    -   iv) R₇ is selected from the group consisting of hydrogen,        halogen, and alkyl,    -   v) R₁₅ and R₁₆ are independently selected from the group        consisting of —OH, alkyloxy, aryloxy, —NH₂, alkylamino,        arylamino, N-aryl-N-alkylamino, —NHNH₂, alkylhydrazino,        arylhydrazino, N-aryl-N-alkylhydrazino, —NHOR₁₇, alkyl, and aryl    -   vi) R₁₇ and R₁₈ are independently selected from the group        consisting of hydrogen, alkyl, and aryl    -   vii) ** represents the point of attachment of the R₁ to the        molecule of formula A;-   b. R₂ is selected from the group consisting of-    wherein:    -   i) R₈, R₉, R₁₀ and R₁₁ are independently selected from the group        consisting of hydrogen, halogen and alkyl,    -   ii) Y₁ and Y₂ are independently O, S, NH, or CH₂, or Y₁ is O, S        or NH, and Y₂ is CH₂, with the proviso that Y₁ and Y₂ cannot        both be O S, or NH if n is 0 or 1, and    -   iii) * represents the point of attachment of the R₂ to the        molecule of formula A-   c. R₃ substituents are independently selected from the group    consisting of alkyl, alkyloxy, and halogen,-   d. R₄ is selected from the group consisting of alkyl, aryl,    heteroaryl, and adamantyl; R₅ is selected from the group consisting    of alkyl, alkyloxy, alkylthio, aryl, and heteroaryl; or R₄ and R₅    may be linked together to form a substituted or unsubstituted 5- or    6-membered cycloalkyl or cycloalkenyl ring, where said substituents    are selected from the group consisting of —OH, ═O, halogen, alkyl,    and where 1 or 2 of the carbon atoms on said 5- or 6-membered    cycloalkyl or cycloalkenyl ring may be optionally replaced by W    where W is selected from the group consisting of O, S, N, NH,    alkylamino, and arylamino;-   e. m and n are independently 0, 1, 2 or 3,    and pharmaceutically acceptable salts thereof.

In another embodiment of the invention, there are provided compoundshaving the structure, selected from the group consisting of compoundshaving formulae B₁, B₂, B₃, B₄, B₅, B₆, B₇, B₈, B₉, and B₁₀

wherein R₁, R₂ and R₃ are as described above and R₁₃ is selected fromthe group consisting of O, S, (CH₃)₂C and CH₂, and R₁₄ is hydrogen ormethyl.

The compounds according to this invention may contain one or moreasymmetric carbon atoms and can thus occur as racemates and racemicmixtures, single enantiomers, diastereomeric mixtures or individualdiastereomers. The term “stereoisomer” refers to a chemical compoundhaving the same molecular weight, chemical composition, and constitutionas another, but with the atoms grouped differently. That is, certainidentical chemical moieties are at different orientations in space and,therefore, when pure, have the ability to rotate the plane of polarizedlight. However, some pure stereoisomers may have an optical rotationthat is so slight that it is undetectable with present instrumentation.The compounds described herein may have one or more asymmetrical carbonatoms and therefore include various stereoisomers. All such isomericforms of these compounds are expressly included in the presentinvention.

Each stereogenic carbon may be of R or S configuration. Although thespecific compounds exemplified in this application may be depicted in aparticular configuration, compounds having either the oppositestereochemistry at any given chiral center or mixtures thereof are alsoenvisioned. When chiral centers are found in the derivatives of thisinvention, it is to be understood that this invention encompasses allpossible stereoisomers.

The terms “optically pure compound” or “optically pure isomer” refers toa single stereoisomer of a chiral compound regardless of theconfiguration of the said compound.

For purpose of this application, all sugars are referenced usingconventional three-letter nomenclature. All sugars are assumed to be inthe D-form unless otherwise noted, except for fucose, which is in theL-form. Further, all sugars are in the pyranose form.

The compounds according to this invention may occur as a mixture oftautomers. The term “tautomer” or “tautomerism” refer to one of two ormore structural isomers that exist in equilibrium and are readilyconverted from one isomeric form to another. Examples of includeketo-enol tautomers, such as acetone/propen-2-ol and the like,ring-chain tautomers, such as glucose/2,3,4,5,6-pentahydroxy-hexanal andthe like. The compounds described herein may have one or more tautomersand therefore include various isomers. All such isomeric forms of thesecompounds are expressly included in the present invention. The followingexample of tautomerism is provided for reference:

The following example of nomenclature and numbering system is providedfor reference.

3-Hydroxy-5,5-dimethyl-2-[4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-carbonyl)-phenyl]-cyclohex-2-enone

The term “substantially homogeneous” refers to collections of moleculeswherein at least 80%, preferably at least about 90% and more preferablyat least about 95% of the molecules are a single compound or a singlestereoisomer thereof.

As used herein, the term “attached” signifies a stable covalent bond,certain preferred points of attachment being apparent to those skilledin the art.

The terms “optional” or “optionally” refer to occurrence ornon-occurence of the subsequently described event or circumstance, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not. In such context, the sentence“optionally substituted alkyl group” means that the alkyl group may ormay not be substituted and the description includes both a substitutedand an unsubstituted alkyl group.

The term “effective amount” of a compound refers a non-toxic butsufficient amount of the compound that provides a desired effect. Thisamount may vary from subject to subject, depending on the species, age,and physical condition of the subject, the severity of the disease thatis being treated, the particular compound used, its mode ofadministration, and the like. Therefore, it is difficult to generalizean exact “effective amount”, yet, a suitable effective amount may bedetermined by one of ordinary skill in the art.

The term “pharmaceutically acceptable” refers to a compound, additive orcomposition that is not biologically or otherwise undesirable. Forexample, the additive or composition may be administered to a subjectalong with a compound of the invention without causing any undesirablebiological effects or interacting in an undesirable manner with any ofthe other components of the pharmaceutical composition in which it iscontained.

The term “pharmaceutically acceptable salts” includes hydrochloric salt,hydrobromic salt, hydroiodic salt, hydrofluoric salt, sulfuric salt,citric salt, maleic salt, acetic salt, lactic salt, nicotinic salt,succinic salt, oxalic salt, phosphoric salt, malonic salt, salicylicsalt, phenylacetic salt, stearic salt, pyridine salt, ammonium salt,piperazine salt, diethylamine salt, nicotinamide salt, formic salt, ureasalt, sodium salt, potassium salt, calcium salt, magnesium salt, zincsalt, lithium salt, cinnamic salt, methylamino salt, methanesulfonicsalt, picric salt, tartaric salt, triethylamino salt, dimethylaminosalt, tris(hydroxymethyl)aminomethane salt and the like. Additonalpharmaceutically acceptable salts are known to those of skill in theart.

When used in conjunction with a compound of this invention, the terms“elicite”, “eliciting,” modulator”, “modulate”, “modulating”,“regulator”, “regulate” or “regulating” selective gene expression referto a compound that can act as an activator, an agonist, a pan-agonist oran antagonist of gene expression by a particular receptor, such as forexample a Retinoid X Receptor and the like.

The terms “therapeutic agent” and “chemotherapeutic agent”, refer to acompound or compounds and pharmaceutically acceptable compositionsthereof that are administered to mammalian subjects as prophylactic orremedy in the treatment of a disease or medical condition. Suchcompounds may.be administered to the subject via oral formulation,transdermal formulation or by injection.

The term “Lewis acid” refers to a molecule that can accept an unsharedpair of electrons and as such would be obvious to one of ordinary skilland knowledge in the art. The definition of “Lewis acid” includes but isnot limited to: boron trifluoride, boron trifluoride etherate, borontrifluoride tetrahydrofuran complex, boron trifluoride tert-butyl-methylether complex, boron trifluoride dibutyl ether complex, borontrifluoride dihydrate, boron trifluoride di-acetic acid complex, borontrifluoride dimethyl sulfide complex, boron trichloride, borontrichloride dimethyl sulfide complex, boron tribromide, boron tribromidedimethyl sulfide complex, boron triiodide, triimethoxyborane,triethoxyborane, trimethylaluminum, triethylaluminum, aluminumtrichloride, aluminum trichloride tetrahydrofuran complex, aluminumtribromide, titanium tetrachloride, titanium tetrabromide, titaniumiodide, titanium tetraethoxide, titanium tetraisopropoxide, scandium(III) trifluoromethanesulfonate, yttrium (III)trifluoromethanesuffonate, ytterbium (III) trifluoromethanesulfonate,lanthanum (III) trifluoromethanesulfonate, zinc (II) chloride, zinc (II)bromide, zinc (II) iodide, zinc (II) trifluoromethanesulfonate, zinc(II) sulfate, magnesium sulfate, lithium perchlorate, copper (II)trifluoromethanesulfonate, copper (II) tetrafluoroborate and the like.Certain Lewis acids may have optically pure ligands attached to theelectron acceptor atom, as set forth in Corey, E. J. Angewandte Chemie,International Edition (2002), 41(10), 1650-1667; Aspinall, H. C.Chemical Reviews (Washington, D.C., United States) (2002), 102(6),1807-1850; Groger, H. Chemistry—A European Journal (2001), 7(24),5246-5251; Davies, H. M. L. Chemtracts (2001), 14(11), 642-645; Wan, Y.Chemtracts (2001), 14(11), 610-615; Kim, Y. H. Accounts of ChemicalResearch (2001), 34(12), 955-962; Seebach, D. Angewandte Chemie,International Edition (2001), 40(1), 92-138; Blaser, H. U. AppliedCatalysis, A: General (2001), 221(1-2), 119-143; Yet, L. AngewandteChemie, International Edition (2001), 40(5), 875-877; Jorgensen, K. A.Angewandte Chemie, International Edition (2000), 39(20), 3558-3588;Dias, L. C. Current Organic Chemistry (2000), 4(3), 305-342; Spindler,F. Enantiomer (1999), 4(6), 557-568; Fodor, K. Enantiomer (1999), 4(6),497-511; Shimizu, K, D.; Comprehensive Asymmetric Catalysis I-III(1999), 3, 1389-1399; Kagan, H. B. Comprehensive Asymmetric CatalysisI-III (1999), 1, 9-30; Mikami, K. Lewis Acid Reagents (1999), 93-136 andall references cited therein. Such Lewis acids maybe used by one ofordinary skill and knowledge in the art to produce optically purecompounds from achiral starting materials.

The term “acylating agent” refers to a molecule that can transfer analkylcarbonyl, substituted alkylcarbonyl or aryl carbonyl group toanother molecule. The definition of “acylating agent” includes but isnot limited to ethyl acetate, vinyl acetate, vinyl propionate, vinylbutyrate, isopropenyl acetate, 1-ethoxyvinyl acetate, trichloroethylbutyrate, trifluoroethyl butyrate, trifluoroethyl laureate, S-ethylthiooctanoate, biacetyl monooxime acetate, acetic anhydride, acetylchloride, succinic anhydride, diketene, diallyl carbonate, carbonic acidbut-3-enyl ester cyanomethyl ester, amino acid and the like.

The term “nucleophile” or “nucleophilic reagent” refers to a negativelycharged or neutral molecule that has an unshared pair of electrons andas such would be obvious to one of ordinary skill and knowledge in theart. The definition of “nucleophile” includes but is not limited to:water, alkylhydroxy, alkoxy anion, arylhydroxy, aryloxy anion,alkylthiol, alkylthio anion, arylthiol, arylthio anion, ammonia,alkylamine, arylamine, alkylamine anion, arylamine anion, hydrazine,alkyl hydrazine, arylhydrazine, alkylcarbonyl hydrazine, arylcarbonylhydrazine, hydrazine anion, alkyl hydrazine anion, arylhydrazine anion,alkylcarbonyl hydrazine anion, arylcarbonyl hydrazine anion, cyanide,azide, hydride, alkyl anion, aryl anion and the like.

The term “electrophile” or “electrophilic reagent” refers to apositively charged or neutral molecule that has an open valence shelland as such would be obvious to one of ordinary skill and knowledge inthe art. The definition of “electrophile” includes but is not limitedto: hydronium, acylium, lewis acids, such as for example, borontrifluoride and the like, halogens, such as for example Br₂ and thelike, carbocations, such as for example tert-butyl cation and the like,diazomethane, trimethylsilyidiazomethane, alkyl halides, such as forexample methyl iodide, benzyl bromide and the like, alkyl triflates,such as for example methyl triflate and the like, alkyl sulfonates, suchas for example ethyl toluenesulfonate, butyl methanesulfonate and thelike, acyl halides, such as for example acetyl chloride, benzoyl bromideand the like, acid anhydrides, such as for example acetic anhydride,succinic anhydride, maleic anhydride and the like, isocyanates, such asfor example methyl isocyanate, phenylisocyanate and the like,chloroformates, such as for example methyl chloroformate, ethylchloroformate, benzyl chloroformate and the like, sulfonyl halides, suchas for example methanesulfonyl chloride, p-tolunesulfonyl chloride andthe like, silyl halides, such as for example trimethylsilyl chloride,tertbutyldimethyl silyll chloride and the like, phosphoryl halide suchas for example dimethyl chlorophosphate and the like,alpha-beta-unsaturated carbonyl compounds such as for example acrolein,methyl vinyl ketone, cinnamaldehyde and the like.

The term “oxidant” refers to any reagent that will increase theoxidation state of a carbon atom in the starting material by eitheradding an oxygen atom to this carbon or removing an electron from thiscarbon and as such would be obvious to one of ordinary skill andknowledge in the art. The definition of “oxidant” includes but is notlimited to: osmium tetroxide, ruthenium tetroxide, rutheniumtrichloride, potassium permanganate, meta-chloroperbenzoic acid,hydrogen peroxide, dimethyl dioxirane and the like.

The term “metal ligand” refers to a molecule that has an unshared pairof electrons and can coordinate to a metal atom and as such would beobvious to one of ordinary skill and knowledge in the art. Thedefinition of “metal ligand” includes but is not limited to: water,alkoxy anion, alkylthio anion, ammonia, trialkylamine, triarylamine,trialkylphosphine, triarylphosphine, cyanide, azide and the like.

The term “reducing reagent” refers to any reagent that will decrease theoxidation state of a carbon atom in the starting material by eitheradding a hydrogen atom to this carbon or adding an electron to thiscarbon and as such would be obvious to one of ordinary skill andknowledge in the art. The definition of “reducing reagent” includes butis not limited to: borane-dimethyl sulfide complex,9-borabicyclo[3.3.1.]nonane (9-BBN), catechol borane, lithiumborohydride, sodium borohydride, sodium borohydride-methanol complex,potassium borohydride, sodium hydroxyborohydride, lithiumtriethylborohydride, lithium n-butylborohydride, sodiumcyanoborohydride, calcium (II) borohydride, lithium aluminum hydride,diisobutylaluminum hydride, n-butyl-diisobutylaluminum hydride, sodiumbis-methoxyethoxyaluminum hydride, triethoxysilane,diethoxymethylsilane, lithium hydride, lithium, sodium, hydrogen Ni/B,and the like. Certain acidic and Lewis acidic reagents enhance theactivity of reducing reagents. Examples of such acidic reagents include:acetic acid, methanesulfonic acid, hydrochloric acid, and the like.Examples of such Lewis acidic reagents include: trimethoxyborane,triethoxyborane, aluminum trichloride, lithium chloride, vanadiumtrichloride, dicyclopentadienyl titanium dichloride, cesium fluoride,potassium fluoride, zinc (II) chloride, zinc (II) bromide, zinc (II)iodide, and the like.

The term “coupling reagent” refers to any reagent that will activate thecarbonyl of a carboxylic acid and facilitate the formation of an esteror amide bond. The definition of “coupling reagent” includes but is notlimited to: acetyl chloride, ethyl chloroformate,dicyclohexylcarbodiimide (DCC), dilsopropyl carbodiiimide (DIC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),N-hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu),4-nitrophenol, pentafluorophenol,2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU), O-benzotriazole-N,N,N′N′-tetramethyluronium hexafluorophosphate(HBTU), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP),benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate,bromo-trispyrrolidino-phosphonium hexafluorophosphate,2-(5-norbomene-2,3-dicarboximido)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TNTU), O-(N-succinimidyl)-1,3,3-tetramethyluroniumtetrafluoroborate (TSTU), tetramethylfluoroformamidiniumhexafluorophosphate and the like.

The term “removable protecting group” or “protecting group” refers toany group which when bound to a functionality, such as the oxygen atomof a hydroxyl or carboxyl group or the nitrogen atom of an amino group,prevents reactions from occurring at these functional groups and whichprotecting group can be removed by conventional chemical or enzymaticsteps to reestablish the functional group. The particular removableprotecting group employed is not critical.

The definition of “hydroxyl protecting group” includes but is notlimited to:

-   a) Methyl, tert-butyl, allyl, propargyl, p-chlorophenyl,    p-methoxyphenyl, p-nitrophenyl, 2,4-dinitrophenyl,    2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl, methoxymethyl,    methylthiomethyl, (phenyidimethylsilyl)methoxymethyl,    benzyloxymethyl, p-methoxy-benzyloxymethyl, p-nitrobenzyloxymethyl,    o-nitrobenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl,    tert-butoxymethyl, 4-pentenyloxymethyl,    tert-butyIdimethylsiloxymethyl, thexyldimethylsiloxymethyl,    tert-butyldiphenylsiloxymethyl, 2-methoxyethoxymethyl,    2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl,    2-(trimethylsilyl)ethoxymethyl, menthoxymethyl, 1-ethoxyethyl,    1-(2-chloroethoxy)ethyl, 1-[2-(trimethylsilyl)ethoxy]ethyl,    1-methyl-1-ethoxyethyl, 1-methyl-1-benzyloxyethyl,    1-methyl-1-benzyloxy-2-fluoroethyl, 1-methyl-1-phenoxyethyl,    2,2,2-trichloroethyl, 1-dianisyl-2,2,2-trichloroethyl,    1,1,1,3,3,3-hexafluoro-2-phenylisopropyl, 2-trimethylsilylethyl,    2-(benzylthio)ethyl, 2-(phenylselenyl)ethyl, tetrahydropyranyl,    3-bromotetrahydropyranyl, tetrahydrothiopyranyl,    1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,    4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydropyranyl    S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]4-methoxypiperidin-4-yl,    1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl,    tetrahydrofuranyl, tetrahydrothiofuranyl and the like;-   b) Benzyl, 2-nitrobenzyl, 2-trifluoromethylbenzyl, 4-methoxybenzyl,    4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl,    4-phenylbenzyl, 4-acylaminobenzyl, 4-azidobenzyl,    4-(methylsulfinyl)benzyl, 2,4-dimethoxybenzyl,    4-azido-3-chlorobenzyl, 3,4-dimethoxybenzyl, 2,6-dichlorobenzyl,    2,6-difluorobenzyl, 1-pyrenylmethyl, diphenylmethyl,    4,4′-dinitrobenzhydryl, 5-benzosuberyl, triphenylmethyl (Trityl),    α-naphthyldiphenylmethyl, (4-Methoxyphenyl)-diphenyl-methyl,    di-(p-methoxyphenyl)-phenylmethyl, tri-(p-methoxyphenyl)methyl,    4-(4′-bromophenacyloxy)-phenyidiphenylmethyl,    4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,    4,4′,4″-tris(levulinoyloxyphenyl)methyl,    4,4′-dimethoxy-3″-[N-(imidazolylmethyl)]trityl,    4,4′-dimethoxy-3″-[N-(imidazolylethyl)carbamoyl]trityl,    1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl,    4-(17-tetrabenzo[a,c,g,l]fluorenylmethyl)-4,4′-dimethoxytrityl,    9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl and the    like;-   c) Trimethylsilyl, triethylsilyl, triisopropylsilyl,    dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl,    tert-butyidimethylsilyl, tert-butyidiphenylsilyl, tribenzylsilyl,    tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,    di-tert-butylmethylsilyl, tris(trimethylsilyl)silyl,    (2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)diisopropylsilyl,    tert-butylmethoxyphenylsilyl, tert-butoxydiphenylsilyl and the like;-   d) —C(O)R₂₀, where R₂₀ is selected from alkyl, substituted alkyl,    aryl and more specifically R₂₀=hydrogen, methyl, ethyl, tert-butyl,    adamantyl, crotyl, chloromethyl, dichloromethyl, trichloromethyl,    trifluoromethyl, methoxymethyl, triphenylmethoxymethyl,    phenoxymethyl, 4-chlorophenoxymethyl, phenylmethyl, diphenylmethyl,    4-methoxycrotyl, 3-phenylpropyl, 4-pentenyl, 4-oxopentyl,    4,4-(ethylenedithio)pentyl,    5-[3-bis(4-methoxyphenyl)hydroxymethylphenoxy]-4-oxopentyl, phenyl,    4-methylphenyl, 4-nitrophenyl, 4-fluorophenyl, 4-chlorophenyl,    4-methoxyphenyl, 4-phenylphenyl, 2,4,6-trimethylphenyl, α-naphthyl,    benzoyl and the like;-   e) —C(O)OR₂₀, where R₂₀ is selected from alkyl, substituted alkyl,    aryl and more specifically R₂₀=methyl, methoxymethyl,    9-fluorenylmethyl, ethyl, 2,2,2-trichloromethyl,    1,1-dimethyl-2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,    2-(phenylsulfonyl)ethyl, isobutyl, tert-Butyl, vinyl, allyl,    4-nitrophenyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl,    4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl,    2-(methylthiomethoxy)ethyl, 2-dansenylethyl, 2-(4-nitrophenyl)ethyl,    2-(2,4-dinitrophenyl)ethyl, 2-cyano-1-phenylethyl, thiobenzyl,    4-ethoxy-1-naphthyl and the like.

The definition of “amino protecting group” includes but is not limitedto:

-   a) 2-methylthioethyl, 2-methylsulfonylethyl,    2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl,    4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl,    1-methyl-1-(triphenylphosphonio)ethyl, 1,1-dimethyl-2-cyanoethyl,    2-dansylethyl, 2-(4-nitrophenyl)ethyl, 4-phenylacetoxybenzyl,    4-azidobenzyl, 4-azidomethoxybenzyl, m-chloro-p-acyloxybenzyl,    p-(dihydrcxyboryl)benzyl, 5-benzisoxazolylmethyl,    2-(trifluoromethyl)-6-chromonytmethyl, m-nitrophenyl,    3.5-dimethoxybenzyl, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl,    o-nitrobenzyl, α-methylnitropiperonyl, 3,4-dimethoxy-6-nitrobenzyl,    N-benzenesulfenyl, N-o-nitrobenzenesulfenyl,    N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl.    N-2-nitro-4-methoxybenzenesulfenyl, N-triphenylmethylsulfenyl,    N-1-(2,2,2-trifluoro-1,1-diphenyl)ethylsulfenyl,    N-3-nitro-2-pyridinesulfenyl, N-p-toluenesulfonyl,    N-benzenesulfonyl, N-2,3,6-trimethyl-4-methoxybenzenesulfonyl,    N-2,4,6-trimethoxybenzene-sulfonyl,    N-2,6-dimethyl-4-methoxybenzenesulfonyl,    N-pentamethyibenzenesulfonyl,    N-2,3,5.6-tetramethyl-4-methoxybenzenesulfonyl and the like;-   b) —C(O)OR₂₀, where R₂₀ is selected from alkyl, substituted alkyl,    aryl and more specifically R₂₀=methyl, ethyl, 9-fluorenylmethyl,    9-(2-sulfo)fluorenylmethyl. 9-(2,7-dibromo)fluorenylmethyl,    17-tetrabenzo[a,c,g,i]fluorenylmethyl. 2-chloro-3-indenylmethyl,    benz[f]inden-3-ylmethyl,    2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothloxanthyl)]methyl,    1,1-dioxobenzo[b]thiophene-2-ylmethyl, 2,2,2-trichloroethyl,    2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,    2-chloroethyl, 1.1-dimethyl-2-haloethyl,    1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl,    1-methyl-1-(4-biphenylyl)ethyl,    1-(3,5di-tert-butylphenyl)-1-methylethyl, 2-(2′-pyridyl)ethyl,    2-(4′-pyridyl)ethyl, 2,2-bis(4′-nitrophenyl)ethyl,    N-(2-pivaloylamino)-1,1-dimethylethyl,    2-[(2-nitrophenyl)dithio]-1-phenylethyl, tert-butyl, 1-adamantyl,    2-adamantyl, Vinyl, allyl, 1-Isopropylallyl, cinnamyl.    4-nitrocinnamyl, 3-(3′-pyridyl)prop-2-enyl, 8-quinolyl,    N-Hydroxypiperidinyl, alkyldithio, benzyl, p-rnethoxybenzyl,    p-nitrobenzyl, p-bromobenzyl. p-chlorobenzyl, 2,4-dichlorobenzyl,    4-methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl, tert-amyl,    S-benzyl thiocarbamate, butynyl, p-cyanobenzyl, cyclobutyl,    cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl,    diisopropylmethyl, 2,2-dimethoxycarbonylvinyl,    o-(N,N′-dimethylcarboxamido)benzyl,    1,1-dimethyl-3-(N,N′-dimethylcarboxamido)propyl,    1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl,    2-lodoethyl, isobomyl, isobutyl, isonicotinyl,    p-(p′-methoxyphenylazo)benzyl, 1-methylcyclobutyl,    1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,    1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,    1-methyl-1-4′-pyridylethyl, phenyl, p-(phenylazo)benzyl,    2,4,6-tri-methylphenyl, 4-(trimethylammonium)benzyl,    2,4,6-trimethylbenzyl and the like.

The definition of “carboxyl protecting group” includes but is notlimited to:

-   2-N-(morpholino)ethyl, choline, methyl, methoxyethyl,    9-Fluorenylmethyl, methoxymethyl, methylthiomethyl,    tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl,    2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, pivaloyloxymethyl,    phenylacetoxymethyl, triisopropylsilylmethyl, cyanomethyl, acetol,    p-bromophenacyl. α-methylphenacyl, p-methoxyphenacyl, desyl,    carboxamidomethyl, p-azobenzenecarboxamido-methyl,    N-phthalimidomethyl, (methoxyethoxy)ethyl, 2,2,2-trichloroethyl,    2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl,    4-chlorobutyl, 5-chloropentyl, 2-(trimethylsilyl)ethyl,    2-methylthioethyl, 1,3-dithianyl-2-methyl,    2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl,    2-(2′-pyridyl)ethyl, 2-(p-methoxyphenyl)ethyl,    2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl,    2-(4-acetyl-2-nitrophenyl)ethyl, 2-cyanoethyl, heptyl, tert-butyl,    3-methyl-3-pentyl, dicyclopropylmethyl, 2,4-dimethyl-3-pentyl,    cyclopentyl, cyclohexyl, allyl, methallyl, 2-methylbut-3-en-2-yl,    3-methylbut-2-(prenyl), 3-buten-1-yl,    4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, α-methylcinnamyl,    propargyl, phenyl, 2,6-dimethylphenyl, 2,6-diisopropylphenyl,    2,6-di-tert-butyl-4-methylphenyl, 2,6-di-tert-butyl-4-methoxyphenyl,    p-(methylthio)phenyl, pentafluorophenyl, benzyl, triphenylmethyl,    diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl,    2-(9,10-dioxo)anthrylmethyl. 5-dibenzosuberyl, 1-pyrenylmethyl,    2-(trifluoromethyl)-6-chromonylmethyl, 2,4,6-trimethylbenzyl,    p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl,    2.6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-Sulfobenzyl,    4-azidomethoxybenzyl,    4-{a/-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino}benzyl,    piperonyl, 4-picolyl, trimethyisilyl, triethylsilyl,    tert-butyldimethylsilyl, isopropyldimethylsilyl,    phenyidimethylsilyl, di-tert-butylmethylsilyl, triisopropylsilyl and    the like.

The term “Amino acid” refers to any of the naturally occurring aminoacids, as well as synthetic analogs and derivatives thereof. Alpha-Aminoacids comprise a carbon atom to which is bonded an amino group, acarboxy group, a hydrogen atom, and a distinctive group referred to as a“side chain”. The side chains of naturally occurring amino acids arewell known in the art and include, for example, hydrogen (e.g., as inglycine), alkyl (e.g., as in alanine, valine, leucine, isoleucine,proline), substituted alkyl (e.g., as in threonine, serine, methionine,cysteine, aspartic acid, asparagine, glutamic acid, glutamine, arginine,and lysine), arylalkyl (e.g., as in phenylalanine), substitutedarylalkyl (e.g., as in tyrosine), heteroarylalkyl (e.g., as intryptophan, histidine) and the like. One of skill in the art willappreciate that the term “amino acid” can also include beta-, gamma-,delta-, omega-amino acids, and the like. Unnatural amino acids are alsoknown in the art, as set forth in, Natchus, M. G. Organic Synthesis:Theory and Applications (2001), 5, 89-196; Ager, D. J. Current Opinionin Drug Discovery & Development (2001), 4(6), 800; Reginato, G. RecentResearch Developments in Organic Chemistry (2000), 4(Pt. 1), 351-359;Dougherty, D. A. Current Opinion in Chemical Biology (2000), 4(6),645-652; Lesley, S. A. Drugs and the Pharmaceutical Sciences (2000),101(Peptide and Protein Drug Analysis), 191-205; Pojitkov, A. E. Journalof Molecular Catalysis B: Enzymatic (2000), 10(1-3), 47-55; Ager, D. J.Speciality Chemicals (1999), 19(1), 10-12, and all references citedtherein. Stereoisomers (e.g., D-amino acids) of the twenty conventionalamino acids, unnatural amino acids such as alpha, alpha-disubstitutedamino acids and other unconventional amino acids may also be suitablecomponents for compounds of the present invention. Examples ofunconventional amino acids include: 4-hydroxyproline, 3-methylhistidine,5-hydroxylysine, and other similar amino acids and imino acids (e.g.,4-hydroxyproline).

The term “N-protected amino acid” refers to any amino acid which has aprotecting group bound to the nitrogen of the amino functionality. Thisprotecting group prevents reactions from occurring at the aminofunctional group and can be removed by conventional chemical orenzymatic steps to reestablish the amino functional group. Theparticular protecting group employed is not critical.

The term “O-protected amino acid” refers to any amino acid which has aprotecting group bound to the oxygen of the carboxyl functionality. Thisprotecting group prevents reactions from occurring at the carboxylfunctional group and can be removed by conventional chemical orenzymatic steps to reestablish the carboxyl functional group. Theparticular protecting group employed is not critical.

The term “Prodrug” refers to an agent that is converted into the parentdrug in vivo. Prodrugs are often useful because, in some situations,they may be easier to administer than the parent drug. They may, forinstance, be bioavailable by oral administration whereas the parent drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. A prodrug may be converted into theparent drug by various mechanisms, including enzymatic processes andmetabolic hydrolysis. See Harper, “Drug Latentiation” in Jucker, ed.Progress in Drug Research 4:221-294 (1962); Morozowich et al.,“Application of Physical Organic Principles to Prodrug Design” in E. B.Roche ed. Design of Biopharmaceutical Properties through Prodrugs andAnalogs, APHA Acad. Pharm. Sci. (1977); Bioreversible Carriers in Drugin Drug Design, Theory and Application, E. B. Roche, ed., APHA Acad.Pharm. Sci. (1987); Design of Prodrugs, H. Bundgaard, Elsevier (1985);Wang et al. “Prodrug approaches to the improved delivery of peptidedrug” in Curr. Pharm. Design. 5(4):265-287 (1999); Pauletti et al.(1997) Improvement in peptide bioavailability: Peptidomimetics andProdrug Strategies, Adv. Drug. Delivery Rev. 27:235-256; Mizen et al.(1998) “The Use of Esters as Prodrugs for Oral Delivery of .beta.-Lactamantibiotics,” Pharm. Biotech. 11,:345-365; Gaignault et al. (1996)“Designing Prodrugs and Bioprecursors I. Carrier Prodrugs,” Pract. Med.Chem. 671-696; Asghamejad, “Improving Oral Drug Transport”, in TransportProcesses in Pharmaceutical Systems, G. L. Amidon, P. I. Lee and E. M.Topp, Eds., Marcell Dekker, p. 185-218 (2000); Balant et al., “Prodrugsfor the improvement of drug absorption via different routes ofadministration”, Eur. J. Drug Metab. Pharmacokinet., 15(2): 143-53(1990); Balimane and Sinko, “Involvement of multiple transporters in theoral absorption of nucleoside analogues”, Adv. Drug Delivery Rev.,39(1-3): 183-209 (1999); Browne, “Fosphenytoin (Cerebyx)”, Clin.Neuropharmacol. 20(1): 1-12 (1997); Bundgaard, “Bioreversiblederivatization of drugs—principle and applicability to improve thetherapeutic effects of drugs”, Arch. Pharm. Chemi 86(1): 1-39 (1979);Bundgaard H. “Improved drug delivery by the prodrug approach”,Controlled Drug Delivery 17: 179-96 (1987); Bundgaard H. “Prodrugs as ameans to improve the delivery of peptide drugs”, Adv. Drug Delivery Rev.8(1): 1-38 (1992); Fleisher et al. “Improved oral drug delivery:solubility limitations overcome by the use of prodrugs”, Adv. DrugDelivery Rev. 19(2): 115-130 (1996); Fleisher et al. “Design of prodrugsfor improved gastrointestinal absorption by intestinal enzymetargeting”, Methods Enzymol. 112 (Drug Enzyme Targeting, Pt. A): 360-81,(1985); Farquhar D, et al., “Biologically ReversiblePhosphate-Protective Groups”, J. Pharm. Sci., 72(3): 324-325 (1983);Freeman S, et al., “Bioreversible Protection for the Phospho Group:Chemical Stability and Bioactivation of Di(4-acetoxy-benzyl)Methylphosphonate with Carboxyesterase,” J. Chem. Soc., Chem. Commun.,875-877 (1991); Friis and Bundgaard, “Prodrugs of phosphates andphosphonates: Novel lipophilic alpha-acyloxyalkyl ester derivatives ofphosphate- or phosphonate containing drugs masking the negative chargesof these groups”, Eur. J. Pharm. Sci. 4: 49-59 (1996); Gangwar et al.,“Pro-drug, molecular structure and percutaneous delivery”, Des.Biopharm. Prop. Prodrugs Analogs, [Symp.] Meeting Date 1976, 409-21.(1977); Nathwani and Wood, “Penicillins: a current review of theirclinical pharmacology and therapeutic use”, Drugs 45(6): 866-94 (1993);Sinhababu and Thakker, “Prodrugs of anticancer agents”, Adv. DrugDelivery Rev. 19(2): 241-273 (1996); Stella et al., “Prodrugs. Do theyhave advantages in clinical practice?”, Drugs 29(5): 455-73 (1985); Tanet al. “Development and optimization of ant-HIV nucleoside analogs andprodrugs: A review of their cellular pharmacology, structure-activityrelationships and pharmacokinetics”, Adv. Drug Delivery Rev. 39(1-3):117-151 (1999); Taylor, “Improved passive oral drug delivery viaprodrugs”, Adv. Drug Delivery Rev., 19(2): 131-148 (1996); Valentino andBorchardt, “Prodrug strategies to enhance the intestinal absorption ofpeptides”, Drug Discovery Today 2(4): 148-155 (1997); Wiebe and Knaus,“Concepts for the design of anti-HIV nucleoside prodrugs for treatingcephalic HIV infection”, Adv. Drug Delivery Rev.: 39(1-3):63-80 (1999);Waller et al., “Prodrugs”, Br. J. Clin. Pharmac. 28: 497-507 (1989).

The terms “halogen”, “halide” or “halo” include fluorine, chlorine,bromine, and iodine.

The terms “alkyl” and “substituted alkyl” are interchangeable andinclude substituted and unsubstituted C₁-C₁₀ straight chain saturatedaliphatic hydrocarbon groups, substituted and unsubstituted C₂-C₁₀straight chain unsaturated aliphatic hydrocarbon groups, substituted andunsubstituted C₄-C₁₀ branched saturated aliphatic hydrocarbon groups,substituted and unsubstituted C₄-C₁₀ branched unsaturated aliphatichydrocarbon groups, substituted and unsubstituted C₃-C₈ cyclic saturatedaliphatic hydrocarbon groups, substituted and unsubstituted C₅-C₈ cyclicunsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms. For example, the definition of “alkyl” shall include butis not limited to: methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu),pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, ethenyl, propenyl,butenyl, penentyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl,undecenyl, isopropyl (i-Pr), isobutyl (i-Bu), tert-butyl (t-Bu),sec-butyl (s-Bu), isopentyl, neopentyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, methylcyclopropyl,ethylcyclohexenyl, butenylcyclopentyl, adamantyl, norbomyl and the like.Alkyl substituents are independently selected from the group consistingof halogen, —OH, —SH, —NH₂, —CN, —NO₂, trihalomethyl, carbamoyl,arylC₀₋₁₀alkyl, heteroarylC₀₋₁₀alkyl, C₁₋₁₀alkyloxy, arylC₀₋₁₀alkyloxy,C₁₋₁₀alkylthio, arylC₀₋₁₀alkylthio, C₁₋₁₀alkylamino,arylC₀₋₁₀alkylamino, N-aryl-N-C₀₋₁₀alkylamino, C₁₋₁₀alkylcarbonyl,arylC₀₋₁₀alkylcarbonyl, C₁₋₁₀alkylcarboxy, arylC₀₋₁₀alkylcarboxy,C₁₋₁₀alkylcarbonylamino, arylC₀₋₁₀alkylcarbonylamino, tetrahydrofuryl,morpholinyl, piperazinyl, hydroxypyronyl, —C₀₋₁₀alkylCOOR₂₁ and—C₀₋₁₀alkylCONR₂₂R₂₃ wherein R₂₁, R₂₂ and R₂₃ are independently selectedfrom hydrogen, alkyl, arylC₀-C₁₀alkyl, or R₂₂ and R₂₃ are taken togetherwith the nitrogen to which they are attached forming a saturated cyclicor unsaturated cyclic system containing 3 to 8 carbon atoms with atleast one substituent as defined herein.

The term “alkyloxy” (e.g. methoxy, ethoxy, propyloxy, allyloxy,cyclohexyloxy) represents a substituted or unsubstituted alkyl group asdefined above having the indicated number of carbon atoms attachedthrough an oxygen bridge. The term “alkyloxyalkyl” represents analkyloxy group attached through an alkyl or substituted alkyl group asdefined above having the indicated number of carbon atoms.

The term “alkylthio” (e.g. methylthio, ethylthio, propylthio,cyclohexenylthio and the like) represents a substituted or unsubstitutedalkyl group as defined above having the indicated number of carbon atomsattached through a sulfur bridge. The term “alkylthioalkyl” representsan alkylthio group attached through an alkyl or substituted alkyl groupas defined above having the indicated number of carbon atoms.

The term “alkylamino” (e.g. methylamino, diethylamino, butylamino,N-propyl-N-hexylamino, (2-yclopentyl)propylamino, hexenylamino, and thelike) represents one or two substituted or unsubstituted alkyl groups asdefined above having the indicated number of carbon atoms attachedthrough an amine bridge. The substituted or unsubstituted alkyl groupsmaybe taken together with the nitrogen to which they are attachedforming a saturated cyclic or unsaturated cyclic system containing 3 to10 carbon atoms with at least one substituent as defined above. The term“alkylaminoalkyl” represents an alkylamino group attached through asubstituted or unsubstituted alkyl group as defined above having theindicated number of carbon atoms.

The term “alkylhydrazino” (e.g. methylhydrazino, diethylhydrazino,butylhydrazino, (2-cyclopentyl)propylhydrazino, cyclohexanehydrazino,and the like) represents one or two substituted or unsubstituted alkylgroups as defined above having the indicated number of carbon atomsattached through a nitrogen atom of a hydrazine bridge. The substitutedor unsubstituted alkyl groups maybe taken together with the nitrogen towhich they are attached forming a saturated cyclic or unsaturated cyclicsystem containing 3 to 10 carbon atoms with at least one substituent asdefined above. The term “alkylhydrazinoalkyl” represents analkylhydrazino group attached through a substituted or unsubstitutedalkyl group as defined above having the indicated number of carbonatoms.

The term “alkylcarbonyl” (e.g. cyclooctylcarbonyl, pentylcarbonyl,3-hexenylcarbonyl and the like) represents a substituted orunsubstituted alkyl group as defined above having the indicated numberof carbon atoms attached through a carbonyl group. The term“alkylcarbonylalkyl” represents an alkylcarbonyl group attached througha substituted or unsubstituted alkyl group as defined above having theindicated number of carbon atoms.

The term “alkylcarboxy” (e.g. heptylcarboxy, cyclopropylcarboxy,3-pentenylcarboxy and the like) represents an alkylcarbonyl group asdefined above wherein the carbonyl is in turn attached through anoxygen. The term “alkylcarbpxyalkyl” represents an alkylcarboxy groupattached through an alkyl group as defined above having the indicatednumber of carbon atoms.

The term “alkylcarbonylamino” (e.g. hexylcarbonylamino,cyclopentylcarbonyl-aminomethyl, methylcarbonylaminophenyl and the like)represents an alkylcarbonyl group as defined above wherein the carbonylis in turn attached through the nitrogen atom of an amino group. Thenitrogen group may itself be substituted with a substituted orulnsubstituted alkyl or aryl group. The term “alkylcarbonylaminoalkyl”represents an alkylcarbonylamino group attached through a substituted orunsubstituted alkyl group as defined above having the indicated numberof carbon atoms.

The term “alkylcarbonylhydrazino” (e.g. ethylcarbonylhydrazino,tert-butylcarbonylhydrazino and the like) represents an alkylcarbonylgroup as defined above wherein the carbonyl is in turn attached throughthe nitrogen atom of a hydrazino group.

The term “aryl” represents an unsubstituted, mono-, di- ortrisubstituted monocyclic, polycyclic, biaryl aromatic groups covalentlyattached at any ring position capable of forming a stable covalent bond,certain preferred points of attachment being apparent to those skilledin the art (e.g., 3-phenyl, 4naphtyl and the like). The arylsubstituents are independently selected from the group consisting ofhalogen, —OH, —SH, —CN, —NO₂, trihalomethyl, hydroxypyronyl, C₁₋₁₀alkyl,arylC₀₋₁₀alkyl, C₀₋₁₀alkyloxyC₀₋₁₀oalkyl, arylC₀₋₁₀alkyloxyC₀₋₁₀alkyl,C₀₋₁₀alkyithioC₀₋₁₀alkyl, arylC₀₋₁₀alkylthioC₀₋₁₀alkyl,C₀₋₁₀alkylaminoC₀₋₁₀alkyl, arylC₀₋₁₀alkylaminoC₀₋₁₀alkyl,N-aryl-N-C₀₋₁₀alkylaminoC₀₋₁₀alkyl, C₁₋₁₀alkylcarbonylC₀₋₁₀alkyl,arylC₀₋₁₀alkylcarbonylC₀₋₁₀alkyl, C₁₋₁₀alkylcarboxyC₀₋₁₀alkyl,arylC₀₋₁₀alkylcarboxyC₀₋₁₀alkyl, C₁₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl,arylC₀₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl, —C₀₋₁₀alkylCOOR₂₁, and—C₀₋₁₀alkylCONR₂₂R₂₃ wherein R₂₁, R₂₂ and R₂₃ are independently selectedfrom hydrogen, C₁-C₁₀alkyl, arylC₀-C₁₀alkyl, or R₂₂ and R₂₃ are takentogether with the nitrogen to which they are attached forming asaturated cyclic or unsaturated cyclic system containing 3 to 8 carbonatoms with at least one substituent as defined above.

The definition of “aryl” includes but is not limited to phenyl,biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl,indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl and thelike.

The term “arylalkyl” (e.g. (4-hydroxyphenyl)ethyl,(2-aminonaphthyl)hexenyl and the like) represents an aryl group asdefined above attached through a substituted or unsubstituted alkylgroup as defined above having the indicated number of carbon atoms.

The term “arylcarbonyl” (e.g. 2-thiophenylcarbonyl,3-methoxyanthrylcarbonyl and the like) represents an aryl group asdefined above attached through a carbonyl group.

The term “arylalkylcarbonyl” (e.g. (2,3-dimethoxyphenyl)propylcarbonyl,(2-chioronaphthyl)pentenyl-carbonyl and the like) represents anarylalkyl group as defined above wherein the alkyl group is in turnattached through a carbonyl.

The term “aryloxy” (e.g. phenoxy, naphthoxy, 3-methylphenoxy, and thelike) represents an aryl or substituted aryl group as defined abovehaving the Indicated number of carbon atoms attached through an oxygenbridge. The term “aryloxyalkyl” represents an aryloxy group attachedthrough a substituted or unsubstituted alkyl group as defined abovehaving the indicated number of carbon atoms.

The term “arylthio” (e.g. phenylthio, naphthylthio, 3-bromophenylthio,and the like) represents an aryl or substituted aryl group as definedabove having the indicated number of carbon atoms attached through asulfur bridge. The term “arylthioalkyln” represents an arylthio groupattached through a substituted or unsubstuted alkyl group as definedabove having the indicated number of carbon atoms.

The term “arylamino” (e.g. phenylamino, diphenylamino, naphthylamino,N-phenyl-N-naphthylamino, o-methylphenylamino, p-methoxyphenylamino, andthe like) represents one or two aryl groups as defined above having theindicated number of carbon atoms attached through an amine bridge. Theterm “arylaminoalkyl” represents an arylamino group attached through asubstituted or unsubstituted alkyl group as defined above having theindicated number of carbon atoms. The term “arylalkylamino” representsan aryl group attached through an alkylamino group as defined abovehaving the indicated number of carbon atoms. The term“N-aryl-N-alkylamino” (e.g. N-phenyl-N-methylamino,N-naphthyl-N-butylamino, and the like) represents one aryl and one asubstituted or unsubstituted alkyl group as defined above having theindicated number of carbon atoms independently attached through an aminebridge.

The term “arylhydrazino” (e.g. phenylhydrazino, naphthylhydrazino,4-methoxyphenylhydrazino, and the like) represents one or two arylgroups as defined above having the indicated number of carbon atomsattached through a hydrazine bridge. The term “arylhydrazinoalkyl”represents an arylhydrazino group attached through a substituted orunsubstituted alkyl group as defined above having the indicated numberof carbon atoms. The term “arylalkylhydrazino” represents an aryl groupattached through an alkylhydrazino group as defined above having theindicated number of carbon atoms. The term “N-aryl-N-alkylhydrazino”(e.g. N-phenyl-N-methylhydrazino, N-naphthyl-N-butylhydrazino, and thelike) represents one aryl and one a substituted or unsubstituted alkylgroup as defined above having the indicated number of carbon atomsindependently attached through an amine atom of a hydrazine bridge.

The term “arylcarboxy” (e.g. phenylcarboxy, naphthylcarboxy,3-fluorophenylcarboxy and the like) represents an arylcarbonyl group asdefined above wherein the carbonyl is in turn attached through an oxygenbridge. The term “arylcarboxyalkyl” represents an arylcarboxy groupattached through a substituted or unsubstituted alkyl group as definedabove having the indicated number of carbon atoms.

The term “arylcarbonylamino” (e.g. phenylcarbonylamino,naphthylcarbonylamino, 2-methylphenylcarbonylamino and the like)represents an arylcarbonyl group as defined above wherein the carbonylis in turn attached through the nitrogen atom of an amino group. Thenitrogen group may itself be substituted with an a substituted orunsubstituted alkyl or aryl group. The term “arylcarbonylaminoalkyl”represents an arylcarbonylamino group attached through a substituted orunsubstituted alkyl group as defined above having the indicated numberof carbon atoms. The nitrogen group may itself be substituted with asubstituted or unsubstituted alkyl or aryl group.

The term “arylcarbonylhydrazino” (e.g. phenylcarbonylhydrazino,naphthylcarbonylhydrazino, and the like) represents an arylcarbonylgroup as defined above wherein the carbonyl is in turn attached throughthe nitrogen atom of a hydrazino group.

The terms “heteroaryl”, “heterocycle” or “heterocyclic” refers to amonovalent unsaturated group having a single ring or multiple condensedrings, from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selectedfrom nitrogen, sulfur or oxygen within the ring. For the purposes ofthis application, the terms “heteroaryl”, “heterocycle” or“heterocyclic” do not include carbohydrate rings (i.e. mono- oroligosaccharides).

Unless otherwise constrained by the definition for the “heteroaryl”substituent, such heterocyclic groups can be optionally substituted with1 to 3 substituents selected from the group consisting of: halogen, —OH,—SH, —CN, —NO₂, trihalomethyl, hydroxypyronyl, C₁₋₁₀alkyl,arylC₀₋₁₀alkyl, C₀₋₁₀alkyloxyC₀₋₁₀alkyl, arylC₀₋₁₀alkyloxyC₀₋₁₀alkyl,C₀₋₁₀alkylthioC₀₋₁₀alkyl, arylC₀₋₁₀alkylthioC₀₋₁₀alkyl,C₀₋₁₀alkylaminoC₀₋₁₀alkyl, arylC₀₋₁₀alkylaminoC₀₋₁₀alkyl,N-aryl-N—C₀₋₁₀alkylaminoC₀₋₁₀alkyl, C₁₋₁₀alkylcarbonylC₀₋₁₀alkyl,arylC₀₋₁₀alkylcarbonylC₀₋₁₀alkyl, C₁₋₁₀alkylcarboxyC₀₋₁₀alkyl,arylC₀₋₁₀alkylcarboxyC₀₋₁₀alkyl, C₁₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl,arylC₀₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl, —C₀₋₁₀alkylCOOR₂₁, and—C₀₋₁₀alkylCONR₂₂R₂₃ wherein R₂₁, R₂₂ and R₂₃ are independently selectedfrom hydrogen, C₁-C₁₀alkyl, arylC₀-C₁₀alkyl, or R₂₂ and R₂₃ are takentogether with the nitrogen to which they are attached forming asaturated cyclic or unsaturated cyclic system containing 3 to 8 carbonatoms with at least one substituent as defined above.

The definition of “heteroaryl” includes but is not limited to thienyl,benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl,benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl,maleimidyl (or pyrrolyl-2,5-dione), 3-pyrrolinyl, indolyl, isoindolyl,3H-indolyl, indolinyl, indolizinyl, indazolyl, phthalimidyl (orisoindoly-1,3-dione), imidazolyl, 2H-imidazolinyl, benzimidazolyl,pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl,isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl,piperonyl, purinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl,isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl,oxadiazolyl, thiadiazolyl and the like.

The term “saturated heterocyclic” represents an unsubstituted, mono-,di- or trisubstituted monocyclic, polycyclic saturated heterocyclicgroup covalently attached at any ring position capable of forming astable covalent bond, certain preferred points of attachment beingapparent to those skilled in the art (e.g., 1-piperidinyl, 4-piperazinyland the like).

The saturated heterocyclic substituents are independently selected fromthe group consisting of halo, —OH, —SH, —CN, —NO₂, trihalomethyl,hydroxypyronyl, C₁₋₁₀alkyl, arylC₀₋₁₀alkyl, C₀₋₁₀alkyloxyC₀₋₁₀alkyl,arylC₀₋₁₀alkyloxyC₀₋₁₀alkyl, C₀₋₁₀alkylthioC₀₋₁₀alkyl,arylC₀₋₁₀alkylthioC₀₋₁₀alkyl, C₀₋₁₀alkylaminoC₀₋₁₀alkyl,arylC₀₋₁₀alkylaminoC₀₋₁₀alkyl, N-aryl-N—C₀₋₁₀alkylaminoC₀₋₁₀alkyl,C₁₋₁₀alkylcarbonylC₀₋₁₀alkyl, arylC₀₋₁₀alkylcarbonylC₀₋₁₀alkyl,C₁₋₁₀alkylcarboxyC₀₋₁₀alkyl, arylC₀₋₁₀alkylcarboxyC₀₋₁₀alkyl,C₁₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl,arylC₀₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl, —C₀₋₁₀alkylCOOR₂₁, and—C₀₋₁₀alkylCONR₂₂R₂₃ wherein R₂₁, R₂₂ and R₂₃ are independently selectedfrom hydrogen, C₁-C₁₀alkyl, arylC₀-C₁₀alkyl, or R₂₂ and R₂₃ are takentogether with the nitrogen to which they are attached forming asaturated cyclic or unsaturated cyclic system containing 3 to 8 carbonatoms with at least one substituent as defined above.

The definition of saturated heterocyclic includes but is not limited topyrrolidinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl,1,4-dithienyl, thiomorpholinyl, piperazinyl, quinuclidinyl and the like.

The term “alpha-beta-unsaturated carbonyl” refers to a molecule that hasa carbonyl group directly attached to a double or triple bonded carbonand which would be obvious to one of ordinary skill and knowledge in theart. The definition of alpha-beta-unsaturated carbonyl includes but isnot limited to acrolein, methyl vinyl ketone, and the like.

Invention aompounds having structure A include

and pharmaceutically acceptable salts thereof

In another embodiment of the invention, there are providedpharmaceutical compositions comprising at least one of the compounds ofthe invention, as well as pharmaceutically acceptable pro-drugs andsalts of such compounds, in a pharmaceutically acceptable vehicle, forenteral, parenteral, topical or ocular administration.

In another embodiment of the invention, there are providedpharmaceutical compositions comprising an effective regulating amount ofat least one of the compounds of the invention in combination with apharmaceutically acceptable carrier, for control of cellular processes,cellular differentiation, cellular proliferation or apoptosis.

In another embodiment of the invention, there are providedpharmaceutical compositions comprising in a pharmaceutically acceptablevehicle suitable for enteral, parenteral, or topical administration, oneor more compounds of the invention for treating a mammalian subjectwherein said wherein said compound exerts its therapeutic effects viathe in vivo modulation of lipid metabolism, lipid homeostasis,hyperlipidemia, skin-related processes, autoimmune diseases, fatty acidmetabolism, malignant cell development, premalignant lesions, programmedcell death, endocrinological processes, or AP-1 metabolism.

In another embodiment of the invention, there are providedpharmaceutical compositions comprising at least one of the compounds ofthe invention, in a pharmaceutically acceptable vehicle, for thetreatment of carcinomas. Examples of carcinomas Include mammary cancer,prostate cancer, kidney cancer, Karposi's sarcoma, colon cancer,cervical cancer, lung cancer, cutaneous T-cell lymphoma, cancer of thehead and neck, cancers of the aerodigestive pathway, skin cancer,bladder cancer, sarcomas, leukoplakias, acute promyelocytic leukemia,and the like.

In another embodiment of the invention, there are providedpharmaceutical compositions comprising at least one the compounds of theinvention in combination with other chemotherapeutic agents, in apharmaceutically acceptable vehicle, for the treatment of carcinomas.Examples of chemotherapeutic agents contemplated for use in the practiceof this particular invention include Busulfan, Carboplatin, Cisplatin,Cyclophosphamide, Cytosine arabinoside, Etoposide, 5-Fluorouracil,Melphalan, Methotrexate, Mitoxantrone, Taxol, Interferon, Fareston,Arzoxifene, Evista, Tamoxifen, and the like.

In another embodiment of the invention, there are providedpharmaceutical compositions comprising at least one the compounds of theinvention in combination with one or more antiestrogenic agents, in apharmaceutically acceptable vehicle, for the treatment of mammarycarcinoma. Examples of antiestrogenic agents contemplated for use in thepractice of this particular invention include Fareston, Arzoxifene,Evista, Tamoxifen, and the like.

In another embodiment of the invention, there are provided cosmeceuticalcompositions comprising at least one the compounds of the invention, ina cosmetically acceptable vehicle, for dermal indications.

In another embodiment, the present invention provides a process forpreparing a compound of formula E. Such a process can be performed, forexample, by contacting a compound of formula C with a compound offormula D under conditions suitable to form compound of formula E, asset forth below:

In the scheme shown above, Z is typically CH, or nitrogen; Y₃ is C₂₋₈alkyl, or C₂₋₈ substituted alkyl, R₂ is typically

R₃ is alkyl, alkyloxy, or halogen; R₄ is alkyl, aryl, heteroaryl, oradamantyl; R₅ is alkyl, alkyloxy, alkylthio, aryl, or heteroaryl; or R₄and R₅ may be linked together to form a substituted or unsubstituted 5-or 6-membered cycloalkyl or cycloalkenyl ring, where said substituentsare selected from the group consisting of —H, ═O, halogen, alkyl, andwhere 1 or 2 of the carbon atoms on said 5- or 6-membered cycloalkyl orcycloalkenyl ring may be optionally replaced by W where W is selectedfrom the group consisting of O, S, N, NH, alkylamino, or arylamino; R₈,R₉, R₁₀ and R₁₁, are each independently hydrogen, halogen and alkyl, Y₁and Y₂ are independently O, S, NH, or CH₂, or Y₁ is O, S or NH, and Y₂is CH₂, with the proviso that Y₁ and Y₂ cannot both be O, S, or NH if nis 0 or 1, R₁₇ and R₁₈ are each independently hydrogen, alkyl, and aryl,R₂₅ is bromo, chloro, alkyl sulfonate, or aryl sulfonate; m and n areindependently 0, 1, 2 or 3, and * represents the point of attachment ofR₂ to the molecules of formula C and E.

Solvents contemplated for use in the practice of this particularinvention process are typically ethereal solvents, such as for example,diethyl ether, dioxane, tetrahydrofuran, and the like, aromaticsolvents, such as for example, toluene, benzene, and the like, andalcoholic solvents, such as for example, tert-butanol and the like, orany suitable mixtures thereof. The process is typically carried out at atemperature in the range of about 25° C. up to about 120° C.

Compound C is typically contacted with compound of formula D in thepresence of a mixture of a palladium catalyst, a ligand and a base.Palladium catalysts contemplated for use in the practice of thisparticular invention process include palladium (II) species such as forexample palladium (II) acetate, tris(dibenzylideneacetone)-dipalladium,palladium (II) acetylacetonate, palladium (II) bromide, palladium (II)chloride, palladium (II) hexafluoroacetylacetonate, palladium (II)sulfate, palladium (II) trifluoroacetate and the like. Ligandscontemplated for use in the practice of this particular inventionprocess include racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,racemic-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,(R)-(+)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,(S)-(−)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,racemic-2-(di-tert-butylphosphino)-1,1′-binaphthyl,(R)-2-(di-tert-butylphosphino)-1,1′-binaphthyl,(S)-2-(di-tert-butylphosphino)-1,1′-binaphthyl,9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene,2,2′-bis-(diphenylphosphino)-1,1′-biphenyl, racemic4,12-bis(diphenylphosphino)-[2.2]-paracyclophane,(R)-(−)-4,12-bis(diphenylphosphino)-[2.2]-paracyclophane,(S)-(+)-4,12-bis(diphenylphosphino)-[2.2]-paracyclophane,2-(di-cyclohexylphosphino)biphenyl,2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-1,1′-biphenyl,2-dicyclohexylphosphino-2′-methyl-1,1′-biphenyl,2-dicyclohexylphosphino-2′-isopropyl-1,1′-biphenyl,(2-dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl,2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl,2-(di-tert-butylphosphino)-1,1′-biphenyl,2-di-tert-butylphosphino-2′-(N,N-dimethylamino)-1,1′-biphenyl,2-di-tert-butylphosphino-2′-methylbiphenyl,2-di-tert-butylphosphino-2′-isopropylbiphenyl,(2-di-tert-butylphosphino)-2′,4′,6′-triisopropyl biphenyl,(2-di-tert-butylphosphino)-2′,6′-dimethoxybiphenyl,2-(diphenylphosphino)biphenyl,2-(diphenylphosphino)-2′-(N,N-dimethylamino)biphenyl,2-di-phenylphosphino-2′-methylbiphenyl,2-di-phenylphosphino-2′-isopropylbiphenyl,(2-diphenylphosphino)-2′,4′,6′-triisopropyl biphenyl,(2-diphenylphosphino)-2′,6′-dimethoxybiphenyl,1,1-bis-(di-tert-butylphosphino)ferrocene,1-diphenylphosphino-2-(di-tert-butylphosphino)-ethylferrocene,tri-tert-butylphosphine, tri-cyclohexylphosphine, and the like. Basescontemplated for use in the practice of this particular inventionprocess include sodium tert-butoxide, potassium tert-butoxide; cesiumcarbonate, potassium carbonate, potassium phosphate tribasic (K₃PO₄),and the like.

In another embodiment, the present invention provides a process forpreparing a compound of formula H. Such a process can be performed, forexample, by contacting a compound of formula F with a compound offormula G under conditions suitable to form compound of formula H, asset forth below:

In the scheme shown above, Z is typically CH, or nitrogen; R₂ istypically

R₃ is alkyl, alkyloxy, or halogen; R₄ is alkyl, aryl, heteroaryl, oradamantyl; R₅ is alkyl, alkyloxy, alkylthio, aryl, or heteroaryl; or R₄and R₅ may be linked together to form a substituted or unsubstituted 5-or 6-membered cycloalkyl or cycloalkenyl ring, where said substituentsare selected from the group consisting of —H, ═O, halogen, alkyl, andwhere 1 or 2 of the carbon atoms on said 5- or 6-membered cycloalkyl orcycloalkenyl ring may be optionally replaced by W where W is selectedfrom the group consisting of O, S, N, NH, alkylamino, or arylamino; R₈,R₉, R₁₀ and R₁₁, are each independently hydrogen, halogen and alkyl, Y₁and Y₂ are independently O, S, NH, or CH₂, or Y₁ is O, S or NH, and Y₂is CH₂, with the proviso that Y₁ and Y₂ cannot both be O, S, or NH if nis 0 or 1, R₁₅ and R₁₆ are each independently —OH, alkyloxy, aryloxy,—NH₂, alkylamino, arylamino, N-aryl-N-alkylamino, —NHNH₂,alkylhydrazino, arylhydrazino, N-aryl-N-alkylhydrazino, —NHOR₁₇, alkyl,and aryl, R₂₅ is bromo, chloro, alkyl sulfonate, or aryl sulfonate; mand n are independently 0, 1, 2 or 3, and * represents the point ofattachment of R₂ to the molecules of formula F and H.

Solvents contemplated for use in the practice of this particularinvention process are typically ethereal solvents, such as for example,diethyl ether, dioxane, tetrahydrofuran, and the like, aromaticsolvents, such as for example, toluene, benzene, and the like, andalcoholic solvents, such as for example, tert-butanol and the like, orany suitable mixtures thereof. The process is typically carried out at atemperature in the range of about 25° C. up to about 120° C.

Compound F is typically contacted with compound of formula G in thepresence of a mixture of a palladium catalyst, a ligand and a base.Palladium catalysts contemplated for use in the practice of thisparticular invention process include palladium (II) species such as forexample palladium (II) acetate, tris(dibenzylideneacetone)-dipalladium,palladium (II) acetylacetonate, palladium (II) bromide, palladium (II)chloride, palladium (II) hexafluoroacetylacetonate, palladium (II)sulfate, palladium (II) trifluoroacetate and the like. Ligandscontemplated for use in the practice of this particular inventionprocess include racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,(R)-(+)-2,2′-bis(diphenylphdsphino)-1,1′-binaphthyl,(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,racemic-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,(R)-(+)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,(S)-(−)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,racemic-2-(di-tert-butylphosphino)-1,1′-binaphthyl,(R)-2-(di-tert-butylphosphino)-1,1′-binaphthyl,(S)-2-(di-tert-butylphosphino)-1,1′-binaphthyl,9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene,2,2′-bis-(diphenylphosphino)-1,1′-biphenyl, racemic4,12-bis(diphenylphosphino)-[2.2]-paracyclophane,(R)-(−)-4,12-bis(diphenylphosphino)-[2.2]-paracyclophane,(S)-(+)-4,12-bis(diphenylphosphino)-[2.2]-paracyclophane,2-(di-cyclohexylphosphino)biphenyl,2-di-cyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,2-di-cyclohexylphosphino-2′-methylbiphenyl,2-di-cyclohexylphosphino-2′-isopropylbiphenyl,(2-dicyclohexylphosphino)-2′,4′,6′-triisopropyl biphenyl,2-(di-tert-butylphosphino)biphenyl,2-di-tert-butylphosphino-2′-(N,N-dimethylamino)biphenyl,2-di-tert-butylphosphino-2′-methylbiphenyl,2-di-tert-butylphosphino-2′-isopropylbiphenyl,(2-di-tert-butylphosphino)-2′,4′,6′-triisopropyl biphenyl2-(di-phenylphosphino)biphenyl,2-(diphenylphosphino)-2′-(N,N-dimethylamino)biphenyl,2-di-phenylphosphino-2′-methylbiphenyl,2-di-phenylphosphino-2′-isopropylbiphenyl,(2-diphenylphosphino)-2′,4′,6′-triisopropyl biphenyl,1,1-bis-(di-tert-butylphosphino)ferrocene,1-diphenylphosphino-2-(di-tert-butylphosphino)-ethylferrocene,tri-tert-butylphosphine, tri-cyclohexylphosphine, and the like. Basescontemplated for use in the practice of this particular inventionprocess include sodium tert-butoxide, potassium tert-butoxide, cesiumcarbonate, potassium carbonate, potassium phosphate tribasic (K₃PO₄),and the like.

Before the present compounds, compositions and methods are disclosed anddescribed, it is to be understood that this invention is not limited tospecific synthetic methods, specific pharmaceutical carriers, or toparticular pharmaceutical formulations or administration regimens, assuch may, of course, vary. It is also to be understood that theterminology used herein Is for the purpose of describing particularembodiments only and is not intended to be limiting.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a bicyclic aromatic compound” includes mixtures ofbicyclic aromatic compounds, reference to “a pharmaceutical carrier”includes mixtures of two or more such carriers, and the like.

Certain pharmaceutically acceptable salts of the invention are preparedby treating the novel compounds of the invention with an appropriateamount of pharmaceutically acceptable base. Representativepharmaceutically acceptable bases are ammonium hydroxide, sodiumhydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide,magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copperhydroxide, aluminum hydroxide, ferric hydroxide, isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine,arginine, histidine, and the like. The reaction is conducted in water,alone or in combination with an inert, water-miscible organic solvent,at a temperature of from about 0° C. to about 100° C., preferably atroom temperature. The molar ratio of compounds of structural formula Ato base used is chosen to provide the ratio desired for any particularsalts. For preparing, for example, the ammonium salts of the startingmaterial, compounds of formula A can be treated with approximately oneequivalent of the pharmaceutically acceptable base to yield a neutralsalt. When calcium salts are prepared, approximately one-half a molarequivalent of base is used to yield a neutral salt, while for aluminumsalts, approximately one-third a molar equivalent of base will be used.

The compounds of the invention according to formula A, including thepharmacologically acceptable pro-drugs or salts thereof, are useful toelicit, modulate and/or regulate selective gene expression by cellularreceptors and provide control over cellular growth, proliferation anddifferentiation processes regulated by certain hormones or vitamins suchas for example all-trans-retinoic acid, 13-cis-retinoic acid,9-cis-retinoic acid, vitamin D, thyroid hormone and the like. As notedabove, the compounds of the invention are thus useful in the treatmentof conditions and/or diseases that are regulated by the aforementionedentities. Examples of such conditions include for example cancer,mammary cancer, prostate cancer, kidney cancer, Karposi's sarcoma, coloncancer, cervical cancer, lung cancer, cutaneous T-cell lymphoma, cancerof the head and neck, cancers of the aerodigestive pathway, skin cancer,bladder cancer, sarcomas, leukoplakias, acute promyelocytic leukemia,acne, psoriasis, aging, wrinkling, diabetes, hyperglycemia, bonecalcification, thyroid conditions, and the like

The compounds of the invention may be conveniently formulated intopharmaceutical compositions composed of one or more of the compoundstogether with a pharmaceutically acceptable carrier as described inRemington's Pharmaceutical Sciences, latest edition, by E. W. Martin(Mack Publ. Co., Easton Pa.).

The compounds of the invention may be administered orally, parenterally(e.g., intravenously), by intramuscular injection, by intraperitonealinjection, topically, transdermally, or the like, although oral ortopical administration is typically preferred. The amount of activecompound administered will, of course, be dependent on the subject beingtreated, the subject's weight, the manner of administration and thejudgment of the prescribing physician. The dosage will be in the rangeof about 2 microgram per kilogram per day to 4 milligram per kilogramper day.

Depending on the intended mode of administration, the pharmaceuticalcompositions may be in the form of solid, semi-solid or liquid dosageforms, such as, for example, tablets, suppositories, pills, capsules,powders, liquids, suspensions, lotions, creams, gels and the like,preferably in unit dosage form suitable for single administration of aprecise dosage. The compositions will include, as noted above, aneffective amount of the selected drug in combination with apharmaceutically acceptable carrier and, in addition, may include othermedicinal agents, pharmaceutical agents, carriers, adjuvants, diluentsand the like.

For solid compositions, conventional non-toxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmaceuticallyadministrable-compositions can, for example, be prepared by dissolving,dispersing, etc., an active compound as described herein and optionalpharmaceutical adjuvants in an excipient, such as, for example, water,saline, aqueous dextrose, glycerol, ethanol, and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like, for example, sodium acetate, sorbitanmonolaurate, triethanolamine sodium acetate, triethanolamine oleate,etc. Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, referenced above.

For oral administration, fine powders or granules may contain diluting,dispersing, and/or surface active agents, and may be presented in wateror in a syrup, in capsules or sachets in the dry state, or in anon-aqueous solution or suspension wherein suspending agents may beincluded, in tablets wherein binders and lubricants may be included, orin a suspension in water or a syrup. Wherever required, flavoring,preserving, suspending, thickening, or emulsifying agents may also beincluded. Tablets and granules are preferred oral administration forms,and these may be coated.

Parenteral administration, if used, is generally characterized byinjection. Injectables can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, as emulsions, or as sustainedrelease delivery system.

EXAMPLES

Used herein, the following abbreviations have the following meanings: Merefers to methyl (CH₃—), Et refers to ethyl (CH₃CH₂—), i-Pr refers toisopropyl ((CH₃)₂CH₂—), t-Bu or tert-butyl refers to tertiary butyl((CH₃)₃CH—), Ph refers to phenyl, Bn refers to benzyl (PhCH₂—), Bzrefers to benzoyl (PhCO—), MOM refers to methoxymethyl, Ac refers toacetyl, TMS refers to trimethylsilyl, TBS refers toter-butyidimethylsilyl, Ms refers to methanesulfonyl (CH₃SO₂—), Tsrefers to p-toluenesulfonyl (p-CH₃PhSO₂—), Tf refers totrifluoromethanesulfonyl (CF₃SO₂—), TfO refers totrifluoromethanesulfonate (CF₃SO₃—), DMF refers toN,N-dimethylformamide, DCM refers to dichloromethane (CH₂Cl₂), THFrefers to tetrahydrofuran, EtOAc refers to ethyl acetate, Et₂O refers todiethyl ether, MeCN refers to acetonitrile (CH₃CN), NMP refers to1-N-methyl-2-pyrrolidinone, DMA refers to N,N-dimethylacetamide, DMSOrefers to dimethylsulfoxide, DCC refers to1,3-dicyclohexyldicarbodiimide, EDCI refers to1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, Boc refers totert-butylcarbonyl, Fmoc refers to 9-fluorenylmethoxycarbonyl, TBAFrefers to tetrabutylammonium fluoride, TBAI refers to tetrabutylammoniumiodide, TMEDA refers to N,N,N,N-tetramethylethylene diamine, Dess-Martinperiodinane or Dess Martin reagent refers to1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)one, DMAP refers to4-N,N-dimethylaminopyridine, (i-Pr)₂NEt or DIEA or Hunig's base refersto N,N-diethylisopropylamine, DBU refers to1,8-Diazabicyclo[5.4.0]undec-7-ene, (DHQ)₂AQN refers to dihydroquinineanthraquinone-1,4-diyl diether, (DHQ)₂PHAL refers to dihydroquininephthalazine-1,4-diyl diether, (DHQ)₂PYR refers to dihydroquinine2,5-diphenyl-4,6-pyrimidinediyl diether, (DHQD)₂AQN refers todihydroquinidine anthraquinone-1,4-diyl diether, (DHQD)₂PHAL refers todihydroquinidine phthalazine-1,4-diyl diether, (DHQD)₂PYR refers todihydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether, LDA refers tolithium diisopropylamide, LITMP refers to lithium2,2,6,6-tetramethylpiperdinamide, n-BuLi refers to n-butyllithium,t-BuLi refers to tert-butyl lithium, IBA refers to1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide, OSO₄ refers to osmiumtetroxide, m-CPBA refers to meta-chloroperbenzoic acid, DMD refers todimethyl dioxirane, PDC refers to pyridinium dichromate, NMO refers toN-methyl morpholine-N-oxide, NaHMDS refers to sodiumhexamethyidisilazide, LiHMDS refers to lithium hexamethyldisilazide,HMPA refers to hexarriethylphosphoramide, TMSCI refers to trimethylsilylchloride, TMSCN refers to trimethylsilyl cyanide, TBSCI refers totert-butyldimethylsilyl chloride, TFA refers to trifluoroacetic acid,TFAA refers to trifluoroacetic anhydride, AcOH refers to acetic acid,Ac₂O refers to acetic anhydride, AcCI refers to acetyl chloride, TsOHrefers to p-toluenesulfonic acid, TsCI refers to p-toluenesulfonylchloride, M.BHA refers to 4-methylbenzhydrylamine, BHA refers tobenzhydrylamine, ZnCl₂ refers to zinc (II) dichloride, BF₃ refers toboron trifluoride, Y(OTf)₂ refers to yttrium (III)trifluoromethanesulfonate, Cu(BF₄)₂ refers to copper (II)tetrafluoroborate, LAH refers to lithium aluminum hydride (LiAlH₄),NaHCO₃ refers to sodium bicarbonate, K₂CO₃ refers to potassiumcarbonate, NaOH refers to sodium hydroxide, KOH refers to potassiumhydroxide, LiOH refers to lithium hydroxide, HCl refers to hydrochloricacid, H₂SO₄ refers to sulfuric acid, MgSO₄ refers to magnesium sulfate,and Na₂SO₄ refers to sodium sulfate. 1H NMR refers to proton nuclearmagnetic resonance, 13C NMR refers to carbon 13 nuclear magneticresonance, NOE refers to nuclear overhauser effect, NOESY refers tonuclear overhauser and exchange spectroscopy, COSY refers to homonuclearcorrelation spectroscopy, HMQC refers to proton detected heteronuclearmultiplet-quantum coherence, HMBC refers to heteronuclear multiple-bondconnectivity, s refers to singlet, bras refers to broad singlet, drefers to doublet, br d refers to broad doublet, t refers to triplet, qrefers to quartet, dd refers to double doublet, m refers to multiplet,ppm refers to parts per million, IR refers to infrared spectrometry, MSrefers to mass spectrometry, HRMS refers to high resolution massspectrometry, EI refers to electron impact, FAB refers to fast atombombardment, CI refers to chemical ionization, HPLC refers to highpressure liquid chromatography, TLC refer to thin layer chromatography,R_(f) refers to, R_(t) refers to retention time, GC refers to gaschromatography, min is minutes, h is hours, rt or RT is roomtemperature, g is grams, mg is milligrams, L is liters, mL ismilliliters, mol is moles and mmol is millimoles.

For all of the following examples, standard work-upland puriflcabonmethods can be utilized and will be obvious to those skilled in the art.Synthetic methodologies that make up the invention are shown in Schemes1-4. These Schemes are intended to describe the applicable chemistrythrough the use of specific examples and are not indicative of the scopeof the invention.

Example 1 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene

To 2,5-dimethyl-2,5-hexanediol (10 g, 68.5 mmol) in a 500 mL flask wasadded reagent grade concentrated HCl (150 mL) and the solution wasstirred at ambient temperature for 1 h. Water (100 mL) and CH₂Cl₂ (100mL) were then added slowly and the layers were separated. The aqueouslayer was washed with additional CH₂Cl₂ (100 mL). The combined organiclayers were dried over MgSO₄ and filtered thru silica gel pad. Thesolvent was removed to yield 10.9 g (87%) of2,5-dichloro-2,5-dimethylhexane. The dichloride was dissolved in 150 mLof CH₂Cl₂ and 9.6 mL of toluene (90 mmol) was added. AlCl₃ (390 mg, 2.9mol) was added in portions over 5 min at ambient temperature. HCl isevolved and the solution tums dark red. The reaction was placed in anice-bath and quenched with deionized water (120 mL). Hexane (150 mL) wasadded and the organic layer was removed. The aqueous layer was washedwith additional hexane (150 mL). The combined organic layers were washedwith water (200 mL) and brine (100 mL) and dried over MgSO₄. The solventwas removed in vacuo to give1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene as a colorless oilthat crystallized after storage at −20° C.

Yield: 12 g (91%); low melting white solid; R_(f)=0.7 in 100% hexane. ¹HNMR (CDCl₃, 300 MHz) δ 1.32 (s, 12H), 1.7 (s, 4H), 2.34 (s, 3H), 6.85(dd, 1H) 7.14 (d, 1H), 7.22 (d, 1H) ¹³C NMR (CDCl₃, 75 MHz) δ 21.54,32.26, 32.32, 34.29, 34.51, 35.57, 35.63, 126.64, 126.75, 127.21,134.93, 142.00, 144.83

Example 2(4-Bromophenyl)-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanone

1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene (2 g, 9.9 mmol) and4-bromobenzoyl chloride (2.17 g, 9.9 mol) were dissolved in 20 mL ofCH₂Cl₂ and cooled to 0° C. using an ice-water-NaCl bath. AlCl₃ (3.95 g,29.7 mmol) was added in portions at over 5 min. The dark reactionmixture was allowed to stir at 0° C. for 5 min. The reaction wasquenched by slow addition of ice at 0° C. The mixture was diluted withwater and 150 mL of EtOAc was added and the layers were separated. Theaqueous layer was washed with additional EtOAc (150 mL). The combinedorganic layers were washed with water (200 mL) and brine (100 mL) anddried over MgSO₄. The filtrate was concentrated in vacuo to yield ayellow foamy solid residue that was recrystallized from MeOH (40 mL).

Yield: 2.85 g (74%); white solid; R_(f)=0.3 in 100% hexane ¹H NMR(CDCl₃, 300 MHz) δ 1.22 (s, 6H), 1.32 (s, 6H), 1.7 (s, 4H), 2.32 (s,3H), 7.18 (s, 1H), 7.22 (s, 1H), 7.59 (d, 2H), 7.68 (d, 2H) ¹³C NMR(CDCl₃, 75 MHz) δ 20.26, 32.01, 32.1, 34.28, 34.71, 35.27, 35.31,128.06, 128.16, 129.51, 131.81, 131.9, 134.32, 135.15, 137.24, 142.04,148.14, 197.46

Example 36-[1-(4Bromophenyl)-vinyl]-1,1,4,4,7-pentamethyl-1,2,3,4-tetrahydro-naphthalene

A solution of(4-bromophenyly(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanone(385 mg, 1 mmol) in 3.7 mL of dry THF was cooled to −78° C. under anatmosphere of nitrogen. A 3.0M solution of MeMgCl in THF (0.517 mL,1.55.mmol) was was added dropwise at −78° C. and the mixture warmed toambient temperature. The reaction was heated to reflux for 10 min,cooled to ambient temperature and quenched with MeOH-EtOAc. The solventwas removed in vacuo, toluene (15 mL) and p-toluenesulfonic acidmonohydrate (0.190 g) were added and the mixture was heated to reflux,allowing the distillate to condense in a Dean-Stark trap prefilled withtoluene. The reation was complete after 1 h and the reaction cooled andwas extracted with water and EtOAc. The organic layer was washed withNaHCO₃ and brine and dried over MgSO₄ and filtered thru a pad of silicagel. The solvent was removed in vacuo and the residue was recrystallizedfrom MeOH.

Yield: 0.355 g (93%); white solid; R_(f)=0.13 in 5% Et₂O-hexane ¹H NMR(CDCl₃, 300 MHz) δ 1.28 (s, 6H),1.31 (s, 6H),1.7 (s, 4H),1.96 (s, 3H),5.22 (d, 1H), 5.7 (d, 1H), 7.05 (s, 1H), 7.08 (s, 1H), 7.15 (d, 2H),7.38 (d, 2H)

Example 44-3-Hydroxy-2-[4-(3,5,5,8,8-pentamethyl-5,6,7,84etrahydronaphthalene-2-carbonyl)-phenyl]-cyclohex-2-enone

A flame-dried Schlenk tube containing a stirbar was charged withPd(OAc)₂ (22.4 mg, 0.1 mmol),(2-dicyclohexylphosphino)-2′,4′,6′-triisopropyl biphenyl (105 mg, 0.22mmol), 1,3-cyclohexanedione (134.4 mg, 1.2 mmol) and finely ground K₃PO₄(490 mg, 2.3 mmol). The tube was capped with a septum, evacuated andbackfilled with nitrogen. A solution of(4-bromopheny)-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-methanonein 3 mL of dry THF was injected and the mixture was stirred at ambienttemperature for 5 min and heated to 80° C. for 1.5 h. The mixture wasthen cooled, diluted with MeOH and filtered. The filtrate wasconcentrated and absorbed on silica gel with MeOH-acetone andchromatographed using MeOH—CH₂Cl₂.

Yield: 191 mg (45%); white solid; R_(f)=0.5 in 10% MeOH—CH₂Cl₂ ¹H NMR(d₆-DMSO, 300 MHz) δ 8 1.18 (s, 6H), 1.28 (s, 6H), 1.65 (s, 4H), 1.94(m, 2H), 2.19 (s, 3H), 2.46 (m, 4H), 7.19 (s, 1H), 7.26 (s, 1H), 7.28(d, 2H), 7.59 (d, 2H) ¹³C NMR (d₆-DMSO, 75 MHz) δ20.04, 21.06, 31.51,32.24, 32.27, 34.38, 34.78, 35.27, 116.08, 126.99, 129.29, 129.39,131.82, 133.36, 135.32, 136.56, 140.65, 141.94, 147.16, 197.84

Example 55-3-Hydroxy-2-{4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-phenyl}-cyclohex-2-enone

A flame-dried Schlenk tube containing a stirbar was charged withPd(OAc)₂ (5.8 mg, 0.026 mmol),(2-dicyclohexylphosphino)-2′,4′,6′-triisopropyl biphenyl (27 mg, 0.057mmol), 1,3-cyclohexanedione (35 mg, 0.313 mmol) and finely ground K₃PO₄(127 mg, 0.6 mmol). The tube was capped with a septum, evacuated andbackfilled with nitrogen. A solution of6-[1-(4-bromophenyl)-vinyl]-1,1,4,4,7-pentamethyl-1,2,3,4-tetrahydro-naphthalenein 3 mL of dry THF was injected and the mixture was stirred at ambienttemperature for 5 min and heated to 80° C. for 5 h. The mixture was thencooled, diluted with MeOH and filtered. The filtrate was concentratedand absorbed on silica gel with MeOH-acetone and chromatographed usingMeOH—CH₂Cl₂.

Yield: 43 mg (40%); White solid; R_(f)=0.5 in 10% MeOH—CH₂Cl₂ ¹H NMR(d₆-DMSO, 300 MHz) δ 1.21 (s, 6H), 1.22 (s, 6H), 1.62 (s, 4H), 1.9 (m,2H), 1.94 (s, 3H), 2.42 (br m, 4H), 5.04 (d, 1H), 5.76 (d, 1H), 7.0-7.12(m, 6H)

Example 66-3-Hydroxy-5,5-dlmethyl-2-{4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-phenyl}-cyclohex-2-enone

A flamedried Schlenk tube containing a stirbar was charged with Pd(OAc)₂(4.4 mg, 0.02 mmol), (2-dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (20 mg, 0.04 mmol), 5,5,-dimethyl-1,3-cyclohexanedione (33 mg,0.235 mmol) and finely ground K₃PO₄ (96 mg, 0.45 mmol). The tube wascapped with a septum, evacuated and backfilled with nitrogen. A solutionof6-[1-(4-bromophenyl)-vinyl]-1,1,4,4,7-pentamethyl-1,2,3,4-tetrahydro-naphthalenein 1 mL of dry THF was injected and the mixture was stirred at ambienttemperature for 5 min and heated to 80° C. for 5 h. The mixture was thencooled, diluted with MeOH and filtered. The filtrate was concentratedand chromatographed using EtOAc-hexane.

Yield: 40 mg (46%); white solid; R_(f)=0.4 in 50% EtOAc-hexane ¹H NMR(CDCl₃, 300 MHz) δ 1.16 (s, 6H), 1.26 (s, 6H), 1.31 (s, 6H), 1.69 (s,4H), 2.01 (s, 3H), 2.38 (br s, 2H), 2.48 (br s, 2H), 5.21 (d, 1H), 5.76(d, 1H), 6.06 (s, 1H), 7.09 (s, 1H), 7.12 (d, 2H), 7.35 (d, 2H)

Example 63-Hydroxy-2-{4-[1(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-phenyl}-cyclopent-2-enone

A flame-dried Schienk tube containing a stirbar was charged withPd(OAc)₂ (4.4 mg, 0.02 mmol),(2-dicyclohexylphosphino)-2′,4′,6′-triisopropyl biphenyl (20 mg, 0.04mmol), 1,3-cyclopentanedione (23 mg, 0.235 mmol) and finely ground K₃PO₄(96 mg, 0.45 mmol). The tube was capped with a septum, evacuated andbackfilled with nitrogen. A solution of6-[1-(4-bromophenyl)-vinyl]-1,1,4,4,7-pentamethyl-1,2,3,4-tetrahydro-naphthalenein 1 mL of dry THF was injected and the mixture was stirred at ambienttemperature for 5 min and heated to 80° C. for 15 h. The mixture wasthen cooled, diluted with MeOH and filtered. The filtrate wasconcentrated and chromatographed using MeOH—CH₂Cl₂.

Yield: 7 mg (10%); white solid; R_(f=)0.5 in 10% MeOH—CH₂Cl₂ ¹H NMR(d₆-acetone, 300 MHz) δ1.28 (s, 6H), 1.32 (s, 6H), 1.74 (s, 4H), 1.98(s, 3H),2.5 (s, 4H), 5.05 (d, 1H), 5.75 (d,1 H), 7.16 (m, 4H), 8.2 (d,2H)

Example 83-Hydroxy-2-[4(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-carbonyl)-phenyl]-cyclohex-2-enonepotassium salt

3-Hydroxy-2-[4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-carbonyl)-phenyl]-cyclohex-2-enone (5.2 mg, 0.0125 mmol) was suspended in 0.5 mLof CH₃CN and treated with 6 μl of 1.79 M aqueous KOH. The mixture wassonicated to homogeneity and the solvent was removed.

Yield: 5.6 mg (99%); yellow oil; MS-ESI positive ion: 455 (M+H)⁺, 417(M+2H-K⁺)⁺; MS-ESI negative ion: 415 (M−K+)

Example 93-Hydroxy-2-{4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-phenyl}-cyclohex-2-enonepotassium salt

3-Hydroxy-2-{4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-phenyl}-cyclohex-2-enone(13.4 mg, 0.032 mmol) was suspended in 3 mL of CH₃CN and treated with 18μl of 1.79 M aqueous KOH. The mixture was sonicated to homogeneity andthe solvent was removed.

Yield: 14 mg (99%); foamy solid;

Example 103-Hydroxy-5,5-dimethyl-2-{4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-phenyl}-cyclohex-2-enonepotassium salt

3-Hydroxy-5,5-dimethyl-2-4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-phenyl}-yclohex-2-enone(5.5 mg, 0.012 mmol) was suspended in 0.5 mL of CH₃CN and treated with6.7 μl of 1.79 M aqueous KOH. The mixture was sonicated to homogeneityand the solvent was removed.

Yield: 15.7 mg (99%); foamy solid

Example 11 A375 Tumor Cell Proliferation Assay

A375 cells (5,000 per well in 90% RPMI-1640 plus 10% Fetal Bovine Serum[FBS]) were pre-incubated in a black clear bottom 96-well plate in anatmosphere of 5% CO₂ at 37° C. for 24 hours. Stock solutions ofcompounds in DMSO were diluted using a buffer and dilutions were addedto each well. The final concentration DMSO in each well did not exceed0.5%. The final assay pH was 7.4. The cells were incubated in RPMI-1640with each compound for an additional 72 to 168 hours. Alamar Blue wasadded and the plate was incubated for an additional 12 hours.Fluorescence intensity was measured using a Gemini plate reader withexcitation at 530 nm and emission at 590 nm. A decrease of 50 percent ormore (≧50%) in fluorescence intensity relative to vehicle treatedcontrols is an indication of significant anti-cancer activity.

Reference Data Compound IC₅₀ (μM) TGI (M) LC₅₀ (μM) Doxorubicin 0.190.30 8.00 Mitomycin 4.20 8.00 10.0

IC₅(50% Inhibitory Concentration): Test compound concentration where theincrease in number or mass of cells from time ₀ to 72 to 168 hours isreduced 50% relative to the corresponding vehicle controls.

TGI (Total Growth Inhibition): Test compound concentration where theincrease in number or mass of cells after 72 to 168 hours is reduced toequal that at time=0. LC₅₀ (50% Lethal Concentration): Test compoundconcentration where the number or mass of cells after 72 to 168 hours isreduced 50% relative to that at time t=0.

Example 12 T47D Tumor Cell Proliferation Assay

T-47D cells (15,000 per well in 90% RPMI-1640 medium plus 10% FetalBovine Serum [FBS]) were pre-incubated in a black clear bottom 96-wellplate in an atmosphere of 5% CO₂ at 37° C. for 24 hours. Stock solutionsof compounds in DMSO were diluted using a buffer and dilutions wereadded to each well in the presence or absence 20 μM Tamoxifen. The finalconcentration DMSO In each well did not exceed 0.5%. The final assay pHwas 7.4. The cells were incubated in RPMI-1640 with each compound for anadditional 72 to 192 hours. Alamar Blue was added and the plate wasincubated for an additional 12 hours. Fluorescence intensity wasmeasured using a Gemini plate reader with excitation at 530 nm andemission at 590 nm. A decrease of 50 percent or more (≧50%) influorescence intensity relative to vehicle treated controls is anindication of significant anti-cancer activity.

Example 13 SCC103 Tumor Cell Proliferation Assay

SCC 103 cells (15,000 per well in 90% EMEM medium plus 10% Fetal BovineSerum [FBS]) were pre-incubated in a black clear bottom 96-well plate inan atmosphere of 5% CO₂ at 37° C. for 24 hours. Stock solutions ofcompounds in DMSO were diluted using a buffer and dilutions were addedto each well. The final concentration DMSO in each well did not exceed0.5%. The final assay pH was 7.4. The cells were incubated in EMEMmedium for an additional 72 hours. Alamar Blue (10% of culture volume)was added and the plate was incubated for an additional 12 hours.Fluorescence intensity was measured using a Gemini plate reader withexcitation at 530 nm and emission at 590 nm. A decrease of 50 percent ormore (≧50%) in fluorescence intensity relative to vehicle treatedcontrols is an indication of significant anti-cancer activity.

Example 14 Radioactive Ligand Binding Assay

[³H]-9 cis-retinoic acid (29 Ci/mmol) and MicroSpin G-25 Columns werepurchased from Amersham Biosciences (Piscataway, N.J.). Unlabeled 9-cisretinoic acid was purchased from Affinity BioReagents (Golden, Colo.).The retinoic acid receptor subtype RXRγ was purchased from BIOMOL(Plymouth Mee ting, Pa.). Stock solution of 9-cis-retinoic acid, wasprepared as either 5 mM ethanol or DMSO stock solutions, and serialdilutions were carried out in 1:1 DMSO-ethanol. The assay bufferconsisted of the following for receptor assay: 8% glycerol, 120 mM KCl,8 mM Tris, 5 mM CHAPS, 4 mM DTT, and 0.24 mM PMSF, pH 7.4, at roomtemperature.

The receptor binding assay was performed with a final volume of 250μcontaining from 10 to 20 μg of protein, plus 10 nM [³H]-9-cis-retinoicacid, RXRγ and varying concentrations of competing ligand (0-1 05 M).Incubations were carried out at 4° C. for 18 h. Equilibrium under theseconditions of buffer and temperature was achieved by 4 h. Non-specificbinding was defined as that binding remaining in the presence of 1000 nMunlabeled 9-cis-retinoic acid. The receptor-ligand complex was separatedfrom unincorporated [3H]-9-cis-retinoic acid by applying the bindingreaction solution to pre-spun MicroSpin G-25 Column and centrifuged at735 G for 2 minutes in a microcentrifuge. The amount of receptor-ligandcomplex was determined by liquid scintillation counting of the purifiedreceptor-ligand complex. After correcting for non-specific binding, theIC₅₀ value was determined. The IC₅₀ value is defined as theconcentration of competing ligand -required to decrease specific bindingby 50%; the IC₅₀ value was determined graphically from a log-logit plotof the data. K_(d) value for 9-cis-retinoic acid using a modifiedCheng-Prussof equation as described by Motulsky.

Although the invention has been described with reference to the aboveexamples, it will be understood that modifications and variations areencompassed within the spirit and scope of the invention. Accordingly,the invention is limited only by the following claims.

1. A compound having the structural formula A

wherein: a. R₁ is selected from the group consisting of substanceshaving formulae A₁, A₂, A₃, A4, A₅, and A₆

 wherein: i) Z is selected from the group consisting of CH, and nitrogenii) Y₃ is selected from the group consisting of C₂₋₈ alkyl, and C₂₋₈substituted alkyl, iii) R₆ is selected from the group consisting of —OH,alkyloxy, aryloxy, alkylcarboxy, arylcarboxy, —SH, alkylthio, arylthio,—NH₂, alkylamino, arylamino, N-aryl-N-alkylamino, —NHNH₂,alkylhydrazino, arylhydrazino, N-aryl-N-alkylhydrazino, —NHOR₁₇,—O(P═O)(OR₁₇)(OR₈), —OCH₂O(P═O)(OR₁₇)(OR₁₈), and —OSO₃R₁₇, iv) R₇ isselected from the group consisting of hydrogen, halogen, and alkyl, v)each of R₁₅ and R16 is independently selected from the group consistingof —OH, alkyloxy, aryloxy, —NH₂, alkylamino, arylamino,N-aryl-N-alkylamino, —NHNH₂, alkylhydrazino, arylhydrazino,N-aryl-N-alkylhydrazino, —NHOR₁₇, alkyl, and aryl, vi) each of R₁₇ andR₁₈ is independently selected from the group consisting of hydrogen,alkyl, and aryl, vii) ** represents the point of attachment of the R₁ tothe molecule of formula A; b. R₂ is selected from the group consistingof

 wherein: i) each of R₈, R₉, R₁₀ and R₁₁ is independently selected fromthe group consisting of hydrogen, halogen and alkyl, ii) each of Y₁ andY₂ is independently O, S, NH, or CH₂, or Y₁ is O, S or NH, and Y₂ isCH₂, with the proviso that Y₁ and Y₂ cannot both be O, S, or NH if n is0 or 1, and iii) * represents the point of attachment of the R₂ to themolecule of formula A c. R3 substituents are independently selected fromthe group consisting of alkyl, alkyloxy, and halogen, d. R₄ is selectedfrom the group consisting of alkyl, aryl, heteroaryl, and adamantyl; R₅is selected from the group consisting of alkyl, alkyloxy, alkylthio,aryl, and heteroaryl; or R₄ and R₅ may be linked together to form asubstituted or unsubstituted 5- or 6-membered cycloalkyl or cycloalkenylring, where said substituents are selected from the group consisting of—OH, ═O, halogen, alkyl, and where 1 or 2 of the carbon atoms on said 5-or 6-membered cycloalkyl or cycloalkenyl ring may be optionally replacedby W where W is selected from the group consisting of O, S, N, NH,alkylamino, and arylamino; e. each of m and n is independently 0, 1, 2or 3, and pharmaceutically acceptable salts thereof.
 2. The compoundaccording to claim 1, having a structure selected from the groupconsisting of substances having formulae B₁, B₂, B₃, B₄, B₅, B₆, B₇, B₈,B₉, and B₁₀

wherein R₁₃ is selected from the group consisting of O, S, (CH₃)₂C andCH₂, and R₁₄ is hydrogen or methyl.
 3. The compound according to claim1, having the structural formula

wherein R₁₃ is selected from the group consisting of O, S, (CH₃)₂C andCH₂.
 4. The compound according to claim 1, having the structural formula

wherein R₁₃ is selected from the group consisting of O, S, (CH₃)₂C andCH₂.
 5. The compound according to claim 1, wherein m is
 0. 6. Thecompound according to claim 1, wherein m is
 1. 7. A compound selectedfrom a group consisting of

and pharmaceutically acceptable salts thereof
 8. A pharmaceuticalcomposition comprising an effective regulating amount of at least onecompound according to claim 1 in combination with a pharmaceuticallyacceptable carrier, for control of cellular processes, cellulardifferentiation, cellular proliferation or apoptosis.
 9. Apharmaceutical composition comprising at least one compound according toclaim 1, in a pharmaceutically acceptable vehicle, for enteral,parenteral, topical or ocular administration.
 10. A pharmaceuticalcomposition comprising at least one compound according to claim 1, in apharmaceutically acceptable vehicle, for the treatment of cancer.
 11. Apharmaceutical composition comprising at least one compound according toclaim 1, in a pharmaceutically acceptable vehicle, for the treatment ofcutaneous T-cell lymphoma, squamous cell carcinoma of the head and neck,lung cancer, mammarycancer, colon cancer, skin cancer, cervical cancer,prostate cancer, kidney cancer, cancers of the aerodigestive pathway,bladder cancer, sarcomas, and/or leukemia.
 12. The pharmaceuticalcomposition according to claim 10, further comprising at least oneadditional chemotherapeutic agent.
 13. The pharmaceutical compositionaccording to claim 12, wherein the additional chemotherapeutic agent isselected from the group comprising Busulfan, Carboplatin, Cisplatin,Cyclophosphamide, Cytosine arabinoside, Etoposide, 5-Fluorouracil,Melphalan, Methotrexate, Mitoxantrone, Taxol, Interferon, Fareston,Arzoxifene, Evista, and Tamoxifen.
 14. The pharmaceutical compositionaccording to claim 12, wherein the additional chemotherapeutic agent isat least one antiestrogenic agent.
 15. A pharmaceutical compositioncomprising at least one compound according to claim 1 in combinationwith at least one other chemotherapeutic selected from the groupconsisting of Fareston, Arzoxifene, Evista, and Tamoxifen, in apharmaceutically acceptable vehicle, for the treatment of mammarycancer.
 16. A cosmeceutical composition comprising at least one compoundaccording to claim 1, in a cosmetically acceptable vehicle, for dermalindications.
 17. A cosmeceutical composition comprising at least onecompound according to claim 1, in a cosmetically acceptable vehicle, forthe treatment of acne and/or psoriasis.
 18. A process for preparing acompound E comprising carrying out a reaction between a compound C and acompound D under conditions suitable to produce the compound E, wherein:

a. R₂ is selected from the group consisting of

 wherein: i) each of R₈, R₉, R₁₀ and R₁₁ is independently selected fromthe group consisting of hydrogen, halogen and alkyl, ii) each of Y₁ andY₂ is independently O, S, NH, or CH₂, or Y₁ is O, S or NH, and Y₂ isCH₂, with the proviso that Y₁ and Y₂ cannot both be O, S, or NH if n is0 or 1, and iii) * represents the point of attachment of the R₂ to themolecule of formula A b. R₃ is selected from the group consisting ofalkyl, alkyloxy, and halogen, c. R₄ is selected from the groupconsisting of alkyl, aryl, heteroaryl, and adamantyl; R₅ is selectedfrom the group consisting of alkyl, alkyloxy, alkylthio, aryl, andheteroaryl; or R₄ and R₅ may be linked together to form a substituted orunsubstituted 5- or 6-membered cycloalkyl or cycloalkenyl ring, wheresaid subs t ituents are selected from the group consisting of —OH, ═O,halogen, alkyl, and where 1 or 2 of the carbon atoms on said 5- or6-membered cycloalkyl or cycloalkenyl ring may be optionally replaced byW where W is selected from the group consisting of O, S, N, NH,alkylamino, and arylamino; d. Z is selected from the group consisting ofCH, and nitrogen; e. Y₃ is selected from the group consisting of C₂₋₈alkyl, and C₂₋₈ substituted alkyl; f. miso, 0, 1, 2 or 3; and g. R₂₅ isselected from a group consisting of bromo, chloro, alkyl sulfonate, andaryl sulfonate.
 19. The process according to claim 18, wherein thereaction is carried out in a solvent or a mixture of solvents selectedfrom the group consisting of dioxane, tetrahydrofuran, toluene, benzene,water and tert-butanol.
 20. The process according to claim 18, whereinthe reaction is carried out between 25° C. and 120° C.
 21. The processaccording to claim 18, wherein the reaction is carried out in thepresence of a mixture of a palladium catalyst, a ligand and a base. 22.The process according to claim 18, wherein the reaction is carried outin the presence of a mixture of a palladium catalyst selected from thegroup consisting of palladium (II) acetate,tris(dibenzylideneacetone)-dipalladium, palladium (II) acetylacetonate,palladium (II) bromide, palladium (II) chloride, palladium (II)hexafluoroacetylacetonate, palladium (II) sulfate, and palladium (II)trifluoroacetate, a ligand selected from the group consisting ofracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,racemic-2,2′-bis(di-p-tolylphosphino l1,1′-binaphthyl,(R)-(+)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,(S)-(−)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,racemic-2-(di-tert-butylphosphino)-1,1′-binaphthyl,(R-2-(di-tert-butylphosphino)-1,1′-binaphthyl,(S)-2-(di-tert-butylphosphino )1,1′-binaphthyl,9,9-Dimethyl4,5-bis(diphenylphosphino)xanthene,2,2′-bis-(diphenylphosphino )-1,1′-biphenyl, racemic 4,12-bis(diphenylphosphino)-[2.2]-paracyclophane,(R)-(−)-4,12-bis(diphenylphosphino)-[2.2]-paracyclophane,(S)-(+)4,12-bis(diphenylphosphino)-[2.2]-paracyclophane,2-(di-cyclohexylphosphino)biphenyl,2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-1,1′-biphenyl,2-dicyclohexylphosphino-2′-methyl-1,1′-biphenyl,2-dicyclohexylphosphino-2′-isopropyl-1,1′-biphenyl,(2-dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl,2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1 ′-biphenyl,2-(di-tert-butylphosphino)-1,1′-biphenyl,2-di-tert-butylphosphino-2′-(N,N-dimethylamino)-1,1′-biphenyl,2-di-tert-butylphosphino-2′-methylbiphenyl,2-di-tert-butylphosphino-2′-isopropylbiphenyl,(2-di-tert-butylphosphino)-2′,4′,6′-triisopropyl biphenyl,(2-di-tert-butylphosphino)-2′,6′-dimethoxybiphenyl,2-(diphenylphosphino)biphenyl,2-(diphenylphosphino)-2′-(N,N-dimethylamino)biphenyl,2-diphenylphosphino-2′-methylbiphenyl,2-diphenylphosphino-2′-isopropylbiphenyl,(2-diphenylphosphino)-2′,4′,6′-triisopropyl biphenyl,(2-diphenylphosphino)-2′,6′-dimethoxybiphenyl,1,1-bis-(di-tert-butylphosphino)ferrocene,1-diphenylphosphino-2-(di-tert-butylphosphino)-ethylferrocene,tri-tert-butylphosphine, and tri-cyclohexylphosphine, and a baseselected from the group consisting of sodium tert-butoxide, potassiumtert-butoxide, cesium carbonate, potassium carbonate, and potassiumphosphate tribasic (K₃PO₄).
 23. The process according to claim 18,wherein the compound E is selected from a group consisting of


24. A process for preparing a compound H comprising carrying out areaction between a compound F with a compound G under conditionssuitable to produce a compound H, wherein

a. R₂ is selected from the group consisting of

 wherein: iv) each of R₈, R₉, R₁₀ and R₁₁ is independently selected fromthe group consisting of hydrogen, halogen and alkyl, v) each of Y₁ andY₂ is independently O, S, NH, or CH₂, or Y₁ is O, S or NH, and Y₂ isCH₂, with the proviso that Y₁ and Y₂ cannot both be O, S, or NH if n is0 or 1, and vi) * represents the point of attachment of the R₂ to themolecule of f ormula A b. R₃ is selected from the group consisting ofalkyl, alkyloxy, and halogen, c. R₄ is selected from the groupconsisting of alkyl, aryl, heteroaryl, and adamantyl; R₅ is selectedfrom the group consisting of alkyl, alkyloxy, alkylthio, aryl, andheteroaryl; or R₄ and R₅ may be linked together to form a substituted orunsubstituted 5- or 6-membered cycloalkyl or cycloalkenyl ring, wheresaid substituents are selected from the group consisting of —OH, ═O,halogen, alkyl, and where 1 or 2 of the carbon atoms on said 5- or6-membered cycloalkyl or cycloalkenyl ring may be optionally replaced byW where W is selected from the group consisting of O, S, N, NH,alkylamino, and arylamino; d. each of R₁₅ and R₁₆ is independentlyselected from the group consisting of —OH, alkyloxy, aryloxy, —NH₂,alkylamino, arylamino, N-aryl-N-alkylamino, —NHNH₂, alkylhydrazino,arylhydrazino, N-aryl-N-alkylhydrazino, —NHOR₁₇, alkyl, and aryl; d. Zis selected from the group consisting of CH, and nitrogen; e. m is 0, 1,2 or 3; and f. R₂₅ is selected from a group consisting of bromo, chloro,alkyl sulfonate, and aryl sulfonate.
 25. The process according to claim24, wherein the. reaction is carried out in a solvent or a mixture ofsolvents selected from the group consisting of dioxane, tetrahydrofuran,toluene, benzene, water and tert-butanol.
 26. The process according toclaim 24, wherein the reaction is carried out between 25° C. and 120° C.27. The process according to claim 24, wherein the reaction is carriedout in the presence of a mixture of a palladium catalyst, a ligand and abase.
 28. The process according to claim 24, wherein the reaction iscarried out in the presence of a mixture of a palladium catalystselected from the group consisting of palladium (II) acetate,tris(dibenzylideneacetone ydipalladium, palladium (II) acetylacetonate,palladium (II) bromide, palladium (II) chloride, palladium (II)hexafluoroacetylacetonate, palladium (II) sulfate, and palladium (II)trifluoroacetate, a ligand selected from the group consisting ofracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,racemic-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,(R)-(+)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,(S)-(−)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,racemic-2-(di-tert-butylphosphino)-1,1′-binaphthyl,(R)-2-(di-tert-butylphosphino)-1,1′-binaphthyl,(S)-2-(di-tert-butylphosphino)-1,1′-binaphthyl,9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene,2,2′-bis-(diphenylphosphino)-1,1′-biphenyl, racemic4,12-bis(diphenylphosphino)-[2.2]-paracyclophane, (R)-(−)-4,12-bis(diphenylphosphino)-[2.2]-paracyclophane,(S)-(+)-4,12-bis(diphenylphosphino)-[2.2]-paracyclophane,2-(di-cyclohexylphosphino)biphenyl,2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-1,1′-biphenyl,2-dicyclohexylphosphino-2′-methyl-1,1′-biphenyl,2-dicyclohexylphosphino-2′-isopropyl-1,1′-biphenyl,(2-dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl,2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl,2-(di-tert-butylphosphino)-1,1′-biphenyl,2-di-tert-butylphosphino-2′-(N,N-dimethylamino)-1,1′-biphenyl,2-di-tert-butylphosphino-2′-methylbiphenyl,2-di-tert-butylphosphino-2′-isopropylbiphenyl,(2-di-tert-butylphosphino)-2′,4′,6′-triisopropyl biphenyl,(2-di-tert-butylphosphino )2′,6′-dimethoxybiphenyl,2-(diphenylphosphino)biphenyl, 2-(diphenylphosphino)-2′-(N,N-dimethylamino)biphenyl, 2-diphenylphosphino-2′-methylbiphenyl,2-diphenylphosphino-2′-isopropylbiphenyl,(2-diphenylphosphino)-2′,4′,6′-triisopropyl biphenyl,(2-diphenylphosphino)-2′,6′-dimethoxybiphenyl,1,1-bis-(di-tert-butylphosphino)ferrocene,1-diphenylphosphino-2-(di-tert-butylphosphino)-ethylferrocene,tri-tert-butylphosphine, and tri-cyclohexylphosphine, and a baseselected from the group consisting of sodium tert-butoxide, potassiumtert-butoxide, cesium carbonate, potassium carbonate, and potassiumphosphate tribasic (K₃PO₄).
 29. The process according to claim 24,wherein the compound H is selected from a group consisting of compoundshaving the formulae


30. A pharmaceutical composition comprising in a pharmaceuticallyacceptable vehicle suitable for enteral, parenteral, or topicaladministration, at least one compound according to claim 1 for treatinga mammalian subject wherein said wherein said compound exerts itstherapeutic effects via the in vivo modulation of lipid metabolism,lipid homeostasis, hyperlipidemia, skin-related processes, autoimmunediseases, fatty acid metabolism, malignant cell development,premalignant lesions, programmed cell death, endocrinological processes,or AP-1 metabolism.
 31. Pharmaceutically acceptable pro-drugs ofcompounds according to claim 1.